Long-Term Administration of Omeprazole-Induced Hypergastrinemia and Changed Glucose Homeostasis and Expression of Metabolism-Related Genes.

Introduction: PPIs, or proton pump inhibitors, are the most widely prescribed drugs. There is a debate regarding the relationship between long-term PPI use and the risk of type 2 diabetes mellitus (T2DM). A potential connection between T2DM and PPIs could be an elevated gastrin concentration. This study is aimed at investigating the long-term effects of PPI omeprazole (OZ) on glucose homeostasis and pancreatic gene expression profile in mice. Methods: Healthy adult male BALB/c mice were randomly divided into three equal groups (n = 10 in each one): (1) experimental mice that received OZ 20 mg/kg; (2) control mice that received 30 µl saline per os; (3) intact mice without any interventions. Mice were treated for 30 weeks. Glucose homeostasis was investigated by fasting blood glucose level, oral glucose tolerance test (GTT), insulin tolerance test (ITT), and basal insulin resistance (HOMA-IR). Serum gastrin and insulin concentration were determined by ELISA. Expressions of Sirt1, Pparg, Nfκb1 (p105), Nfe2l2, Cxcl5, Smad3, H2a.z, and H3f3b were measured by RT-PCR. Result: The ROC analysis revealed an increase in fasting blood glucose levels in OZ-treated mice in comparison with control and intact groups during the 30-week experiment. A slight but statistically significant increase in glucose tolerance and insulin sensitivity was observed in OZ-treated mice within 30 weeks of the experiment. The mice treated with OZ exhibited significant increases in serum insulin and gastrin levels, accompanied by a rise in the HOMA-IR level. These animals had a statistically significant increase in Sirt1, Pparg, and Cxcl5 mRNA expression. There were no differences in ß-cell numbers between groups. Conclusion: Long-term OZ treatment induced hypergastrin- and hyperinsulinemia and increased expression of Sirt1, Pparg, and Cxcl5 in mouse pancreatic tissues accompanied by specific changes in glucose metabolism. The mechanism of omeprazole-induced Cxcl5 mRNA expression and its association with pancreatic cancer risk should be investigated.

Azithromycin with scaling and root planing versus scaling and root planing alone in the treatment of periodontitis: A randomized controlled trial.

Background: The growing interest in the possibilities of macrophages modulation with therapeutic purposes promotes new approaches for periodontitis treatment. Aim: The aim of this randomized controlled open clinical study was to evaluate the early clinical and immunological effects of the long-course azithromycin as an adjunct to scaling and root planing in periodontitis. Methods: 50 patients (with stage I-III, grade A/B periodontitis) and 22 periodontally healthy volunteers as the reference group were recruited. Following scaling and root planing (SRP), the patients were randomly assigned to one of two treatment modalities: SRP only (n = 25) and adjunct azithromycin (Az) treatment (n = 25). The patients were monitored at baseline, and 30 ± 5 days after therapy. Clinical attachment loss (CAL), periodontal probing depth (PPD) and bleeding on probing (BoP) were evaluated. Secondary outcome measures included mean changes in single-positive CD68 + and CD163 + macrophages (Mφs) density and ratio, evaluated by immunohistochemistry, and IL1-ß, IL-6, IL-10, TGF-ß levels, detected by ELISA. Results: At 1 month both groups showed significant improvements of CAL, PPD and BoP, without significant added benefit in terms of CAL, PPD and BoP of Az. But Az increased the density of CD68 + and CD163 + Mφs (P < 0.0001), decreased the CD68+/CD163 + ratio (P = 0.043), decreased IL-1ß (P < 0.01), IL-6 (P < 0.001) levels, and increased IL-10 (P < 0.0001) and TGF-ß (P < 0.001) levels compared to SRP and periodontitis at baseline. Conclusion: The long course of Az demonstrated modulation of CD68 + and CD163 + Mφs towards M2 polarization, which may play a significant role in achieving favorable long-term treatment outcomes. ClinicalTrials.gov.

PPARG stimulation restored lung mRNA expression of core clock, inflammation- and metabolism-related genes disrupted by reversed feeding in male mice.

The circadian rhythm system regulates lung function as well as local and systemic inflammations. The alteration of this rhythm might be induced by a change in the eating rhythm. Peroxisome proliferator-activated receptor gamma (PPARG) is a key molecule involved in circadian rhythm regulation, lung functions, and metabolic processes. We described the effect of the PPARG agonist pioglitazone (PZ) on the diurnal mRNA expression profile of core circadian clock genes (Arntl, Clock, Nr1d1, Cry1, Cry2, Per1, and Per2) and metabolism- and inflammation-related genes (Nfe2l2, Pparg, Rela, and Cxcl5) in the male murine lung disrupted by reversed feeding (RF). In mice, RF disrupted the diurnal expression pattern of core clock genes. It decreased Nfe2l2 and Pparg and increased Rela and Cxcl5 expression in lung tissue. There were elevated levels of IL-6, TNF-alpha, total cells, macrophages, and lymphocyte counts in bronchoalveolar lavage (BAL) with a significant increase in vascular congestion and cellular infiltrates in male mouse lung tissue. Administration of PZ regained the diurnal clock gene expression, increased Nfe2l2 and Pparg expression, and reduced Rela, Cxcl5 expression and IL-6, TNF-alpha, and cellularity in BAL. PZ administration at 7 p.m. was more efficient than at 7 a.m.

PPARG agonist pioglitazone influences diurnal kidney medulla mRNA expression of core clock, inflammation-, and metabolism-related genes disrupted by reverse feeding in mice.

This study examined the influence of PPARG activation by pioglitazone (PG) on the mRNA of core clock, inflammation- and metabolism-related genes in the mouse kidney medulla as well as urinary sodium/potassium excretion rhythms disrupted by reverse feeding. Mice were assigned to daytime feeding and nighttime feeding groups. PG 20 mg/kg was administered at 7 am or 7 pm. On day 8 of the feeding intervention, mice were killed at noon and midnight. Kidney medulla expression of Arntl, Clock, Nr1d1, Cry1, Cry2, Per1, Per2, Nfe2l2, Pparg, and Scnn1g was determined by qRT PCR. We measured urinary K+ , Na+ , urine volume, food, and H2 O intake. The reverse feeding uncoupled the peripheral clock gene rhythm in mouse kidney tissues. It was accompanied by a decreased expression of Nfe2l2 and Pparg as well as an increased expression of Rela and Scnn1g. These changes in gene expressions concurred with an increase in urinary Na+ , K+ , water excretion, microcirculation disorders, and cell loss, especially in distal tubules. PG induced the restoration of diurnal core clock gene expression as well as Nfe2l2, Pparg, Scnn1g mRNA, and decreased Rela expressions, stimulating Na+ reabsorption and inhibiting K+ excretion. PG intake at 7 pm was more effective than at 7 am.

Quantitative assessment of CD68+ AND CD163+ macrophages in the primary focus and metastatic lesions of regional lymph nodes in non-luminal her2-positive invasive breast carcinoma

Introduction: Introduction: Tumor-associated macrophages are an important prognostic factor and have been shown to be associated with invasion and migration of various types of cancer. Unlike M1-macrophages, which have pro-inflammatory and anti-cancer activity, M2-macrophages are immunosuppressive, promoting the restoration of the intracellular matrix, and therefore they contribute to the tumor growth. The aim: To study the quantitative characteristic and localization of CD68+ and CD163+ M2-like TAM that infiltrate non-luminal HER2-enriched carcinomas of BC in the primary focus without metastases and in paired specimens with metastases in the lymph nodes, as well as the pathomorphological characteristics of this type of BC. Material and methods: The material of the study were intraoperative tissues of tumors and ipsilateral lymph nodes at radical removal of mammary glands. Immunohistochemical characteristics of the removed tumors (ER, PR, HER2, Ki67) were used to organize two groups of patients with primary BC according to the N1 / 0 status. Results: The statistical processing of the entire set of digital data confirmed a significant increase in CD68+TAM, but not CD163+M2 under metastatic conditions (p <0.0001), which may suggest an increase in M1-type TAM and their promotion of metastases in non-luminal HER2-enriched BC. Analysis of peculiarities of TAM localization showed that CD68+TAM was localized by clusters within the tumor nests and adjacent stroma, necrotized nests, whereas the typical localization of CD163+TAM M2-like macrophages predominated in the stroma and near the necrotic sites (where their quantitative characteristics coincide with those of CD68+TAM). This may indicate a relative predominance of M1 macrophages precisely in tumor nests. Along with the results on increased CD68+TAM (but not CD163+TAM) in metastases, it is possible to assume the contribution of M1 macrophages to the development / metastasis of BC, as prognosticated for other tumors. Conclusions: A significant decrease in the number of CD68+TAM in metastases of the lymph node as compared with the primary clusters of BC, along with the absence of correlations, may reflect other functions of TAM in the affected lymph nodes or change of the tumor type in the metastasis.

Difficulties in Diagnosis of Sialolithiasis: A Case Series.

Sialolithiasis is one of the most common and extensively obstructive disorders of the major salivary glands. Here, we report 3 cases of sialolithiasis in the submandibular salivary gland showing symptomatic similarities to other dental and non-dental disorders of the maxillofacial area. How the various clinical features of this condition and findings on 3D-CT may lead to a misdiagnosis are also discussed. In the first case, that of a 45-year-old woman, a final diagnosis of a non-radiopaque submandibular sialolith allowed the initially indicated surgical extraction of a malerupted and semi-impacted right mandibular 3rd molar to be abandoned. In the second case, that of a 57-year-old woman, radiographic findings had previously led to a diagnosis of ameloblastoma, which had masked the presence of sialolithiasis for at least 9 years, despite the radiopacity of the sialolith. Meanwhile, exacerbation of sialolithiasis was mistaken for lymphadenitis. In the third case, that of a 40-year-old woman, sialolithiasis was diagnosed in a timely manner, despite the fact that the dentists' attention had initially been focused on odontopathological symptoms. One feature of the present report is the concurrence of dental and non-dental pathologies affecting the same sextant as the sialolithiasis. Despite recent advances in imaging technology and diagnostics, cases of sialolithiasis being misdiagnosed continue to occur in clinical practice.