Targeting LRP6: A new strategy for cancer therapy.

Targeting specific molecular drivers of tumor growth is a key approach in cancer therapy. Among these targets, the low-density lipoprotein receptor-related protein 6 (LRP6), a vital component of the Wnt signaling pathway, has emerged as an intriguing candidate. As a cell-surface receptor and vital co-receptor, LRP6 is frequently overexpressed in various cancer types, implicating its pivotal role in driving tumor progression. The pursuit of LRP6 as a target for cancer treatment has gained substantial traction, offering a promising avenue for therapeutic intervention. Here, this comprehensive review explores recent breakthroughs in our understanding of LRP6's functions and underlying molecular mechanisms, providing a profound discussion of its involvement in cancer pathogenesis and drug resistance. Importantly, we go beyond discussing LRP6's role in cancer by discussing diverse potential therapeutic approaches targeting this enigmatic protein. These approaches encompass a wide spectrum, including pharmacological agents, natural compounds, non-coding RNAs, epigenetic factors, proteins, and peptides that modulate LRP6 expression or disrupt its interactions. In addition, also discussed the challenges associated with developing LRP6 inhibitors and their advantages over Wnt inhibitors, as well as the drugs that have entered phase II clinical trials. By shedding light on these innovative strategies, we aim to underscore LRP6's significance as a valuable and multifaceted target for cancer treatment, igniting enthusiasm for further research and facilitating translation into clinical applications.

Pantoprazole suppresses carcinogenesis and growth of hepatocellular carcinoma by inhibiting glycolysis and Na+/H+ exchange.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The prevention and therapy for this deadly disease remain a global medical challenge. In this study, we investigated the effect of pantoprazole (PPZ) on the carcinogenesis and growth of HCC. Both diethylnitrosamine (DEN) plus CCl4-induced and DEN plus high fat diet (HFD)-induced HCC models in mice were established. Cytokines and cell proliferation-associated gene in the liver tissues of mice and HCC cells were analyzed. Cellular glycolysis and Na+/H+ exchange activity were measured. The preventive administration of pantoprazole (PPZ) at a clinically relevant low dose markedly suppressed HCC carcinogenesis in both DEN plus CCl4-induced and HFD-induced murine HCC models, whereas the therapeutic administration of PPZ at the dose suppressed the growth of HCC. In the liver tissues of PPZ-treated mice, inflammatory cytokines, IL1, CXCL1, CXCL5, CXCL9, CXCL10, CCL2, CCL5, CCL6, CCL7, CCL20, and CCL22, were reduced. The administration of CXCL1, CXCL5, CCL2, or CCL20 all reversed PPZ-suppressed DEN plus CCL4-induced HCC carcinogenesis in mice. PPZ inhibited the expressions of CCNA2, CCNB2, CCNE2, CDC25C, CDCA5, CDK1, CDK2, TOP2A, TTK, AURKA, and BIRC5 in HCC cells. Further results showed that PPZ reduced the production of these inflammatory cytokines and the expression of these cell proliferation-associated genes through the inhibition of glycolysis and Na+/H+ exchange. In conclusion, PPZ suppresses the carcinogenesis and growth of HCC, which is related to inhibiting the production of inflammatory cytokines and the expression of cell proliferation-associated genes in the liver through the inhibition of glycolysis and Na+/H+ exchange.

Combined effect of pantoprazole and mesenchymal stem cells on experimentally induced gastric ulcer: implication of oxidative stress, inflammation and apoptosis pathways.

Gastric ulcer (GU) is one of the most common diseases of the upper gastrointestinal tract that affects millions of people worldwide. This study aimed to investigate the possible alleviating effect of a combined treatment of pantoprazole (PANTO) and adipose tissue-derived mesenchymal stem cells (ADSCs) in comparison with each treatment alone on the healing process of the experimentally induced GU in rats, and to uncover the involved pathways. Rats were divided into five groups: (1) Control, (2) GU, (3) PANTO, (4) ADSCs and (5) ADSCs + PANTO. Markers of oxidative stress, inflammation and apoptosis were assessed. The current data indicated that PANTO-, ADSCs- and ADSCs + PANTO-treated groups showed significant drop (p < 0.05) in serum advanced oxidation protein products (AOPPs) and advanced glycation end products (AGEPs) along with significant elevation (p < 0.05) in serum TAC versus the untreated GU group. Moreover, the treated groups (PANTO, ADSCs and ADSCs + PANTO) displayed significant down-regulation (p < 0.05) in gastric nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor alpha (TNF-α), cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1), matrix metallopeptidase 9 (MMP-9) and caspase-3 along with significant up-regulation (p < 0.05) in vascular endothelial growth factor (VEGF) and peroxisome proliferator-activated receptor gamma (PPARγ) genes expression compared to the untreated GU group. Immunohistochemical examination of gastric tissue for transforming growth factor ß1 (TGF-ß1), epidermal growth factor (EGF) and proliferating cell nuclear antigen (PCNA) showed moderate to mild and weak immune reactions, respectively in the PANTO-, ADSCs- and ADSCs + PANTO-treated rat. Histopathological investigation of gastric tissue revealed moderate to slight histopathological alterations and almost normal histological features of the epithelial cells, gastric mucosal layer, muscularis mucosa and submucosa in PANTO-, ADSCs- and ADSCs + PANTO-treated rats, respectively. Conclusively, the co-treatment with ADSCs and PANTO evidenced sententious physiological protection against GU by suppressing oxidative stress, inhibiting inflammation and reducing apoptosis with consequent acceleration of gastric tissue healing process.

Associations between enteral nutrition and outcomes in the SUP-ICU trial: Protocol for exploratory post hoc analyses.

Critically ill patients are at risk of gastrointestinal (GI) bleeding. Counter measures to minimise this risk include the use of pharmacological stress ulcer prophylaxis (SUP). The effect of enteral nutrition as SUP on GI bleeding event rates is unknown. There are conflicting data describing the effect of co-administration of enteral nutrition with pharmacological SUP, and there is substantial variation in practice. We aim to conduct an exploratory post hoc analysis to evaluate the association of enteral nutrition with clinically important GI bleed rates in ICU patients included in the SUP-ICU trial, and to explore any interactions between enteral nutrition and pharmacologic SUP on patient outcomes. The SUP-ICU trial dataset will be used to assess if enteral nutrition is associated with the outcomes of interest. Extended Cox models will be used considering relevant competing events, including treatment allocation (SUP or placebo) and enteral nutrition as a daily time-varying covariate, with additional adjustment for severity of illness (SAPS II). Results will be presented as adjusted hazard ratios for treatment allocation and enteral nutrition, and for treatment allocation and enteral nutrition considering potential interactions with the other variable, all with 95% confidence intervals and p-values for the tests of interaction. All results will be considered as exploratory only. This post hoc analysis may yield important insights to guide practice and inform the design of future randomised clinical trial investigating the effect of enteral nutrition on GI bleeding.

Chronic Tubulointerstitial Nephritis and Peripheral Neuropathy Probably Due to Pantoprazole Mimicking Systemic Disease.

The coexistence of peripheral neuropathy and chronic tubulointerstitial nephritis in a patient can be secondary to various diseases including-connective tissue disorders, sarcoidosis, IgG4-related disease, heavy metal poisoning, plasma cell dyscrasias, and drugs. A 70-year old woman was admitted with fatigue for 4 months and numbness of both lower limbs for 6 months. She had antral gastritis and was on treatment with pantoprazole for 1 year. On evaluation, she had peripheral neuropathy and chronic tubulointerstitial nephritis which was suspected to be secondary to pantoprazole after ruling out other causes. We present a patient with multiple complications (peripheral neuropathy and chronic tubulointerstitial nephritis) likely associated with pantoprazole which was not reported in the literature previously to the best of our knowledge.

Proton pump inhibitors and osteoporosis risk: exploring the role of TRPM7 channel.

BACKGROUND: Long-term use of proton pump inhibitors (PPIs) has been linked to an increased risk of osteoporosis, with various indirect mechanisms so far identified. Although no direct underlying mechanism for effect on bone cells have been investigated with the use of PPIs. Melastatin-like transient receptor potential 7 (TRPM7)channel has been engaged in the proliferation of bone cells. TRPM7 channel is regulated by extracellular Mg2+ and Ca2+ level, that further encourages to analyse if any imbalance with pantoprazole usage could alter bone remodelling process mediated by TRPM7. OBJECTIVES: The present study was conducted to investigate the effect of pantoprazole on the calcium and magnesium level, the cations involved in the bone remodelling process, as well as role of the TRPM7 channel in the proliferation of bone cells. METHODS: A cytotoxicity study was carried out to study the effect of pantoprazole on the bone cell using MC3T3-E1 cell line, together with the expression of TRPM7 was determined post-pantoprazole treatment. An in vivo study in rats was carried out for estimation of Ca2+, Mg2+ and Ca2+/Mg2+ ratio as well as bone strength was measured over a duration of 4 weeks and 8 weeks with the treatment of pantoprazole. A pilot-scale clinical study was carried out in patients with a fracture to support the evidence of preliminary findings from in-vitro and in vivo studies. RESULTS: MC3T3-E1 cell line treated with pantoprazole showed decreased cell viability in a dose-dependent manner and reduced expression of TRPM7 channel, evidencing interaction of TRPM7 and pantoprazole in the bone remodelling process. A pilot study conducted on 12 patients having major fractures showed changes in serum Mg2+ and Ca2+ levels over a period of 1 month as well as the animal study also showed ionic imbalance over 8-week treatment with pantoprazole. Bone density measured for the patient at the end of the 1-month treatment was found to be in the osteopenic category, together with the animal study which showed a decrease in femur bone strength for the animal treated with pantoprazole over a period of 8 weeks. CONCLUSION: The study findings proved a negative impact of pantoprazole use on Ca2+ and Mg2+ levels, which can impact TRPM7-mediated bone remodelling which serves to be a possible mechanism for osteoporosis upon pantoprazole use.

Utilization trend of gastric acid-suppressing agents in relation to analgesics.

BACKGROUND: Controversies exist about excessive use of gastric acid-suppressing agents or lack of adequate indications, especially when co-prescribed with analgesics for gastroprotection. We aimed to analyze the nationwide trend of gastric acid-suppressing agents and analgesics. METHODS: We obtained nationwide consumption data of analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs], opioids, others) and gastric acid-suppressing agents (proton pump inhibitors [PPI] and histamine-2 receptor antagonists [H2RAs]) between years of 2014-2018 from IQVIA Turkey. Drug utilization was measured by defined daily dose (DDD)/1000 inhabitants/day (DID) unit. Drug sales data were further used to test the correlation of PPIs and H2RAs to analgesics. RESULTS: During the study period, analgesic utilization increased from 65.7 to 67.4 DID. NSAIDs constituted 82.7%-84.9% of all analgesic utilization. The consumption of NSAIDs increased by 3.1%, and the most commonly consumed analgesic was diclofenac (18.5 ± 1.5 DID), constituting 25.4%-29.0% of all analgesics. PPI utilization was found to regularly raise from 52.1 DID in 2014 to 72.0 DID in 2018 with an overall increment of 38.2%. Use of H2RAs was found to increase from 11.4 DID in 2014 to 14.0 DID in 2018. The physician visit-adjusted utilization of both antirheumatic NSAIDs and non-antirheumatic analgesics showed significantly moderate-strong positive correlations with PPIs (r: 0.63, 0.48-0.76 and r: 0.63, 0.47-0.75, respectively) and H2RAs (r: 0.61, 0.44-0.73 and r: 0.57, 0.41-0.71, respectively). CONCLUSION: The utilization trend exhibited a dramatic increase of the gastric acid-suppressing agents -more pronounced for PPIs, with a modest increase in analgesics. Excessive utilization of PPIs does not seem to imply a tendency toward only NSAID-related gastroprotection.

Interactions in clinical trials: Protocol and statistical analysis plan for an explorative study of four randomized ICU trials on use of pantoprazole, oxygenation targets, haloperidol and intravenous fluids.

BACKGROUND: Intensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Co-enrolment in randomized clinical trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations. METHODS: This protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90-day all-cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention-to-treat populations of the four trials will be included. Four co-primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the co-interventions with interactions terms. The primary analytical measure of interest will be the analyses' tests of interaction. A p-value below .05 will be considered statically significant. The stratification variable- and co-intervention-adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity. CONCLUSION: This exploratory analysis will investigate the presence of any interactions between pantoprazole, oxygenation targets, haloperidol and amount of intravenous fluids in four international ICU trials using co-enrolment. Assessment of possible interactions represents valuable information to guide the design, statistical powering and conduct of future trials.

Unusual severe gastritis and gastric ulcers caused by pembrolizumab.

Pembrolizumab (an immune checkpoint inhibitor)-related gastritis and gastric ulcers are rare immune-related adverse events, which are insufficiently treated with proton pump inhibitors (PPIs) therapy alone, and usually require systemic steroid therapy and even other biological agents (such as infliximab) in severe cases. Here, we report a case of 49-years-old woman suffering from gastritis and gastric ulcers after pembrolizumab treatment, which was refractory to 2 months of PPI therapy. The diagnosis was made by the clinical and histopathologic presentations. She had immediate resolution of abdominal symptoms after initiation of steroid treatment, but the gastritis and gastric ulcers improved slowly and lasted for months as shown in endoscopy. She was finally treated with extended steroid therapy without serious complications. We discuss the latest treatment options and our management strategies of the case.

Vincamine Modulates the Effect of Pantoprazole in Renal Ischemia/Reperfusion Injury by Attenuating MAPK and Apoptosis Signaling Pathways.

Pantoprazole has an antioxidant function against reactive oxygen species (ROS). Vincamine, a herbal candidate, is an indole alkaloid of clinical use against brain sclerosis. The aim of the present experiment is to evaluate, on a molecular level for the first time, the value of vincamine in addition to pantoprazole in treating experimentally induced renal ischemia/reperfusion injury (IRI). One-hundred-and-twenty-eight healthy male Wistar albino rats were included. Serum creatinine, blood urea nitrogen, and malondialdehyde levels were assessed. ELISA was used to estimate the pro-inflammatory cytokines. The expression of Bcl-2 and Bax genes was assessed by quantitative real-time PCR. ERK1/2, JNK1/2, p38, cleaved caspase-3, and NF-κB proteins expressions were estimated using western blot assay. The kidneys were also histopathologically studied. The IRI resulted in impaired cellular functions with increased creatinine, urea nitrogen, malondialdehyde, TNF-α, IL-6, and IL-1ß serum levels, and up-regulated NF-ĸB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins. Furthermore, it down-regulated the expression of the Bcl-2 gene and upregulated the Bax gene. The treatment with vincamine, in addition to pantoprazole multiple doses, significantly alleviated the biochemical and histopathological changes more than pantoprazole or vincamine alone, whether the dose is single or multiple, declaring their synergistic effect. In conclusion, vincamine with pantoprazole multiple doses mitigated the renal IRI through the inhibition of apoptosis, attenuation of the extracellular signaling pathways through proinflammatory cytokines' levels, and suppression of the MAPK (ERK1/2, JNK, p38)-NF-κB intracellular signaling pathway.

Repurposing pantoprazole and haloperidol as efflux pump inhibitors in azole resistant clinical Candida albicans and non-albicans isolates.

Candida species have a major role in nosocomial infections leading to high morbidity and mortality. Increased resistance to various antifungals, especially azoles is a significant problem. One of the main mechanisms for azole resistance is the up-regulation of efflux pump genes including CDR1 and MDR1. In the current study, clinical Candida isolates were identified to the species level and the antifungal susceptibility (AFS) of different Candida species was determined by disk diffusion method. Furthermore, the main mechanisms of azole resistance were investigated. Finally, haloperidol and pantoprazole were tested for their potential synergistic effect against fluconazole-resistant isolates. One hundred and twenty-two Candida clinical isolates were used in this study. 70 isolates were Candida albicans (57.4%), the non-albicans Candida species include: C. krusei (20.5%), C. tropicalis (6.6%), C. parapsilosis (5.7%), C. dubliniensis (4.9%) and C. glabrata (4.9%). The AFS testing showed that resistance to fluconazole and voriconazole were 13.1% (n = 16) and 9.8% (n = 12), respectively. Among the 16 resistant isolates, eight isolates (50%) were strong biofilm producers, seven (43.8 %) formed intermediate biofilm and one had no biofilm. All resistant strains overexpressed efflux pumps. Using RT-PCR, the efflux genes CDR1, MDR1 and ABC2 were over-expressed in azole resistant isolates. Haloperidol-fluconazole and pantoprazole-fluconazole combinations reduced the MIC of fluconazole in resistant isolates. The current study showed an increase in azole resistance of Candida species. The majority of resistant isolates form biofilm, and overexpress efflux pumps. Pantoprazole and Haloperidol showed a noteworthy effect as efflux pump inhibitors which oppose the fluconazole resistance in different Candida species.

Pre-Endoscopy Use of Proton Pump Inhibitor Intravenous Bolus Dosing in Hemodynamically Stable Patients With Suspected Upper Gastrointestinal Bleeding: Results of a Pharmacist-Managed Hospital Protocol to Reduce Continuous Infusion Pantoprazole Use.

Background: Guidelines for acute upper gastrointestinal bleeding (UGIB) recommend use of proton pump inhibitors (PPI) administered by continuous IV infusion (CI). Although data suggest comparable outcomes with CI and IV push (IVP) dosing post-endoscopy, there are limited data to support IVP PPI as the pre-endoscopy regimen. Objective: To evaluate the impact of a pharmacist-managed protocol for reducing PPI CIs and substitution of PPI IVP dosing in hemodynamically stable patients with suspected acute upper gastrointestinal bleeding (UGIB) prior to endoscopic intervention. Design, Setting, and Participants: Retrospective study; Tertiary-care community teaching hospital; Hemodynamically stable adults with confirmed or suspected UGIB. Hemodynamic stability was defined as a systolic blood pressure >90 mmHg, heart rate <100 beats, mean arterial pressure >65 mmHg, and no requirement for vasopressors. Intervention: All iterations of treatment recommendations encouraged an initial pantoprazole 80 mg IVP dose. In the pre-intervention group, patients were then treated at the at the provider's discretion with the majority receiving CI pantoprazole. After implementation of the original protocol (Phase I), all hemodynamically stable patients were allowed 1 bag of CI pantoprazole (80 mg infused over 10 hours) before being transitioned by the pharmacist to pantoprazole 40 mg IVP every 12 hours. After internal analysis, the protocol was revised to allow patients to be immediately transitioned to IVP dosing without an initial CI (Phase II). Main Outcome: Incidence of continued bleeding or re-bleeding within 7 days of initial PPI dose. Results: A total of 325 patients were included across all 3 study phases. The median number of CI bags per patient was reduced from 4 pre-intervention, to 1.5 in phase I, and to 0 in phase II (P < .001). The primary endpoint of continued bleeding or re-bleeding within 7 days was similar across all 3 groups (5.0% vs 6.5% vs 5.2%, P = .92). Mean intravenous pantoprazole costs were reduced by $21.73/patient. Conclusions: Movement toward preferential use of IVP PPI prior to endoscopy for hemodynamically stable patients with confirmed or suspected UGIBs resulted in similar rates of continued bleeding or re-bleeding and generated modest cost savings. These findings warrant further investigation.

The impact of a 1-hour time interval between pazopanib and subsequent intake of gastric acid suppressants on pazopanib exposure.

Co-treatment with gastric acid suppressants (GAS) in patients taking anticancer drugs that exhibit pH-dependant absorption may lead to decreased drug exposure and may hamper drug efficacy. In our study, we investigated whether a 1-hour time interval between subsequent intake of pazopanib and GAS could mitigate this negative effect on drug exposure. We performed an observational study in which we collected the first steady-state pazopanib trough concentration (Cmin ) levels from patients treated with pazopanib 800 mg once daily (OD) taken fasted or pazopanib 600 mg OD taken with food. All patients were advised to take GAS 1 hour after pazopanib. Patients were grouped based on the use of GAS and the geometric (GM) Cmin levels were compared between groups for each dose regimen. Additionally, the percentage of patients with exposure below the target threshold of 20.5 mg/L and the effect of the type of PPI was explored. The GM Cmin levels were lower in GAS users vs non-GAS users for both the 800 and 600 mg cohorts (23.7 mg/L [95% confidence interval [CI]: 21.1-26.7] vs 28.2 mg/L [95% CI: 25.9-30.5], P = .015 and 26.0 mg/L [95% CI: 22.4-30.3] vs 33.5 mg/L [95% CI: 30.3-37.1], P = .006). Subtherapeutic exposure was more prevalent in GAS users vs non-GAS users (33.3% vs 19.5% and 29.6% vs 14%). Sub-analysis showed lower GM pazopanib Cmin in patients who received omeprazole, while minimal difference was observed in those receiving pantoprazole compared to non-users. Our research showed that a 1-hour time interval between intake of pazopanib and GAS did not mitigate the negative effect of GAS on pazopanib exposure and may hamper pazopanib efficacy.

The Effects of Proton Pump Inhibitors (Pantoprazole) on Pentylenetetrazole-Induced Epileptic Seizures in Rats and Neurotoxicity in the SH-SY5Y Human Neuroblastoma Cell Line.

Recent studies have shown that proton pump inhibitors have positive effects on the nervous system. However, its effect on epileptic seizure and neuronal damage are still unclear. In this study, it was aimed to investigate the effect of pantoprazole on pentylenetetrazole-induced epileptic seizures in rats and neurotoxicity in the SH-SY5Y cell line. Animals were divided into three groups: control, saline (1 mL/kg serum physiologic), and pantoprazole (10 mg/kg). Pentylenetetrazole (45 mg/kg) was given to induce a seizure and a passive avoidance test trial was carried out to evaluate memory function. 8-hydroxy-2'-deoxyguanosine (8-OHdG), caspase-3, and brain-derived neurotrophic factor (BDNF) levels were measured in the brain by commercial kits. SH-SY5Y cells were treated with saline or pantoprazole for one hour, and then pentylenetetrazole (30 µm) was added to the medium to induce neurotoxicity. After 24 h, cell viability, total antioxidant, total oxidant status, and apoptosis were measured in SH-SY5Y cells. It was found that pantoprazole treatment postponed epileptic seizure onset, protected memory, reduced 8-OHdG, caspase-3, and also increased BDNF in the brain. In addition, it blocked pentylenetetrazole toxicity, apoptosis, increased antioxidant, and decreased oxidant status in SH-SY5Y cells. Pantoprazole significantly improved seizure, oxidative stress, and apoptosis. Thus, pantoprazole could be used as a supportive therapeutic agent in epilepsy.

Pantoprazole ameliorates liver fibrosis and suppresses hepatic stellate cell activation in bile duct ligation rats by promoting YAP degradation.

Liver fibrosis is one of the most severe pathologic consequences of chronic liver diseases, and effective therapeutic strategies are urgently needed. Proton pump inhibitors (PPIs) are H+/K+-ATPase inhibitors and currently used to treat acid-related diseases such as gastric ulcers, which have shown other therapeutic effects in addition to inhibiting acid secretion. However, few studies have focused on PPIs from the perspective of inhibiting hepatic fibrosis. In the present study, we investigated the effects of pantoprazole (PPZ), a PPI, against liver fibrosis in a bile duct ligation (BDL) rat model, human hepatic stellate cell (HSC) line LX-2 and mouse primary HSCs (pHSCs), and explored the potential mechanisms underlying the effects of PPZ in vitro and in vivo. In BDL rats, administration of PPZ (150 mg· kg-1· d-1, i.p. for 14 d) significantly attenuated liver histopathological injury, collagen accumulation, and inflammatory responses, and suppressed fibrogenesis-associated gene expression including Col1a1, Acta2, Tgfß1, and Mmp-2. In LX-2 cells and mouse pHSCs, PPZ (100-300 µM) dose-dependently suppressed the levels of fibrogenic markers. We conducted transcriptome analysis and subsequent validation in PPZ-treated LX-2 cells, and revealed that PPZ inhibited the expression of Yes-associated protein (YAP) and its downstream targets such as CTGF, ID1, survivin, CYR61, and GLI2. Using YAP overexpression and silencing, we demonstrated that PPZ downregulated hepatic fibrogenic gene expression via YAP. Furthermore, we showed that PPZ promoted the proteasome-dependent degradation and ubiquitination of YAP, thus inhibiting HSC activation. Additionally, we showed that PPZ destabilized YAP by disrupting the interaction between a deubiquitinating enzyme OTUB2 and YAP, and subsequently blocked the progression of hepatic fibrosis.

Effects of Low-Dose Amitriptyline on Epigastric Pain Syndrome in Functional Dyspepsia Patients.

AIM: To observe the therapeutic effect of low-dose amitriptyline (AMT) on epigastric pain syndrome (EPS) in patients with functional dyspepsia. METHODS: Sixty patients with EPS were randomly divided into the following two groups for a four-week clinical trial: routine treatment with pantoprazole (RT group) and the AMT group. The RT group was treated with 40 mg of pantoprazole once daily. The AMT group received 25 mg of AMT once daily before bedtime. The Nepean Dyspepsia Index (NDI) checklist, Hamilton Rating Scale of Anxiety/Depression (HAMA/HAMD), and Pittsburgh Sleep Quality Index (PSQI) were employed to evaluate dyspepsia symptoms, psychological distress, and sleep, respectively. RESULTS: All items were similar between the two groups before treatment (0 week). After 4 weeks of treatment, the NDI-symptom checklist score as well as the severity and bothersomeness of EPS in the AMT group was significantly decreased compared with those in the RT group (p < 0.05). However, no differences were found in the frequency of NDI checklist, psychological status (HAMD/HAMA scores) of EPS, or sleep quality (PSQI score) between the two groups after treatment. In addition, the time to fall asleep was shorter in the AMT group compared with the RT group after 4 weeks of treatment (p < 0.05). CONCLUSION: Low-dose AMT effectively improved the dyspepsia symptoms and the time to fall asleep in the EPS patients, compared with pantoprazole, although it did not reduce the psychological distress. Therefore, AMT could be considered as a good candidate for EPS treatment in the clinic.

Pantoprazole Attenuates MAPK (ERK1/2, JNK, p38)-NF-κB and Apoptosis Signaling Pathways after Renal Ischemia/Reperfusion Injury in Rats.

Ischemia/reperfusion injury (IRI) in the kidney is the most common cause of acute renal dysfunction through different cell damage mechanisms. This study aimed to investigate, on molecular basics for the first time, the effect of pantoprazole on renal IRI in rats. Different biochemical parameters and oxidative stress markers were assessed. ELISA was used to estimate proinflammatory cytokines. qRT-PCR and western blot were used to investigate the gene and protein expression. Renal histopathological examination was also performed. IRI resulted in tissue damage, elevation of serum levels of creatinine, urea nitrogen, malondialdehyde, TNF-α, IL-6, IL-1ß, up-regulation of NF-κB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins. Furthermore, it up-regulated the expression of the Bax gene and down-regulated the expression of the Bcl-2 gene. Treatment of the injured rats with pantoprazole, either single dose or multiple doses, significantly alleviated IRI-induced biochemical and histopathological changes, attenuated the levels of proinflammatory cytokines, down-regulated the expression of NF-κB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins, and the Bax gene, and up-regulated Bcl-2 gene expression. Moreover, treatment with pantoprazole multiple doses has an ameliorative effect that is greater than pantoprazole single-dose. In conclusion, pantoprazole diminished renal IRI via suppression of apoptosis, attenuation of the pro-inflammatory cytokines' levels, and inhibition of the intracellular signaling pathway MAPK (ERK1/2, JNK, p38)-NF-κB.

INFLUENCE OF THE DURABLE APPLICATION OF PROTONIC PUMP INHIBITORS ON CYTOKINE CONCENTRATION IN RAT BLOOD SERUM.

OBJECTIVE: The aim: Of the work was to determine the content of pro- and anti-inflammatory cytokines in the blood serum of the control group rats and after 28 days of inhibiting HCl secretion in the stomach by proton pump blockers "Omeprazole" and "Pantoprazole". PATIENTS AND METHODS: Materials and methods: The studies were performed on 30 white non-linear male rats weighing 160-180 g, divided into three groups with 10 animals in each. The control (group 1) were injected intraperitoneally with water for injections within 28 days once a day. Group 2 was administered omeprazole. Group 3 was administered pantoprazole. The concentration of cytokines in the blood serum of rats was determined by the enzyme immunoassay method. For statistic data processing, Student's t-criterion for independent samples was applied. RESULTS: Results: After prolonged administration of omeprazole and pantoprazole, the blood serum concentrations of IFNγ, TNFα, IL-1 in rats increased by 58.5% and 3.41%, 73.3% and 48.4%, 80.2% and 40.8%, respectively, and IL-12B 40p decreased by 36.6% when using omeprazole and was almost indistinguishable from the control values when pantoprazole was administered. With administration of omeprazole, IL-4 concentration decreased by 39.8% and that of pantoprazole increased by 3.86% compared to the control. Administration of omeprazole and pantoprazole did not affect IL-6 concentration. CONCLUSION: Conclusion: Inhibition of hydrochloric acid secretion in the stomach of rats for 28 days using omeprazole and pantoprazole led to an imbalance between pro- and anti-inflammatory cytokines. The adverse effect of pantoprazole was less pronounced than that of omeprazole.

MORPHOLOGICAL CHANGES OF THE GASTRIC MUCOSA WHILE USING ANTIAGGREGANTS AND PANTOPRAZOLE (AN EXPERIMENTAL STUDY).

OBJECTIVE: The aim: Was to characterize the morphological peculiarities of the gastric mucosa at early stage of prescription of acetylsalicylic acid (ASA) and clopidogrel as well as to study the impact of pantoprazole on the gastric mucosa to optimize the prophylaxis and treatment of gastropathies induced by ASA and clopidogrel. PATIENTS AND METHODS: Materials and methods: The experiments were performed on 77 non-linear white male rats with the average weight of 150-180 g. Depending on the aim of research, the animals were divided into 7 groups. RESULTS: Results: The administration of pantoprazole in combination with ASA and clopidogrel presented positive trends in neutral glycoproteins amount and contributes to preventing GM necrotic lesions by amplification of protective properties of mucus and stabilization of apoptotic activity of gastric epithelial cells. CONCLUSION: Conclusions: 1. According to our study findings, administration of ASA in combination with clopidogrel results in 2,5 times higher risk of GM erosive lesions. 2. One of the most significant morphological manifestations of gastropathy in ASA and clopidogrel regimen is the development of microerosions, which are poorly diagnosed by macroscopic examination. 3. The use of PAS-reaction makes possible to identify damage to the basal membrane of superficial epitheliocytes, which may be a top-priority morphological criterion of gastropathy induced by ASA or clopidogrel in the absence of an inflammatory reaction. 4. Administration of pantoprazole in combination with ASA and clopidogrel contributes to preventing GM necrotic lesions by amplification of protective properties of mucus and stabilization of apoptotic activity of gastric epithelial cells.

Effects of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of proton pump inhibitors.

Proton pump inhibitors (PPIs) are used widely for the treatment of acid-related disorders. Despite their excellent efficacy and tolerance, the pharmacodynamics and pharmacokinetics of PPIs are affected by each patient's CYP2C19 and gastric H+,K+-ATPase genotype. The aim of this review was to analyze the effect of genetic polymorphisms on the pharmacodynamic and pharmacokinetic properties of PPIs. The gastric acid-suppressive effect of PPIs is affected by both gastric H+,K+-ATPase and CYP2C19 polymorphisms, although gastric H+,K+-ATPase polymorphisms may have larger effects. Ilaprazole and rabeprazole show relatively small differences in the pharmacokinetic and pharmacodynamic properties and clinical efficacy among the different CYP2C19 genotypes. Compared with oral administration, the intravenous infusion of PPIs is less affected by CYP2C19 polymorphism. At the same dose, each enantiomer has less variation among different CYP2C19 genotypes than a racemate mixture.