Human pepsinogens: A review of clinical and genetic aspects

In recent years clinical interest in the study of the proteolytic enzymes of the stomach has greatly increased. Human pepsinogens belong to the group of aspartic proteases and are categorized into two main groups: Pepsinogen A (PGA = PG I) and Pepsinogen C (PGC = PG II). Genetic models have been proposed to explain the inheritance of PGA, and a recent multigene model may be of value. PGA phenotypes in urine and gastric mucosa have been determined in healthy volunteers as well as in patients with different gastric disorders. An increased frequency of the ‘intense Pg5’ phenotype seems to be associated with gastric cancer and pre-malignant conditions, such as atrophic gastritis. Reliable radio-immunoassay and enzyme-linked immunosorbent assay techniques have facilitated the study of serum levels of PGA and PGC in different patient groups; in particular, duodenal ulcer patients (high PGA levels) and patients with atrophic gastritis and/or gastric cancer (low PGA levels). The ratio serum PGA/PGC may be introduced for clinical application, being the most convenient non-invasive marker for the detection of fundic atrophy. While the chromosome localization of pepsinogen has been established, further research is likely to concentrate on the structure and organization of the pepsinogen genes at the DNA-level, as well as on the development of new isozyme specific monoclonal antibodies.     

Seroprevalence ofHelicobacter pylori and association with atrophic gastritis in patients with Sjögren’s syndrome

To investigate the association betweenHelicobacter pylori (HP) infection and atrophic gastritis in Sjögren’s syndrome (SS), we conducted an age-matched case-control study examining serum HP-IgG antibodies and pepsinogen (PG) I and II levels using ELISA. The sera of 82 primary SS (1-SS), and 57 secondary SS (2-SS) were studied, as well as 198 controls having a diagnosis of connective tissue disease (CTD), except for SS which were obtained according to age. The titers of HP-IgG in 1-SS were significantly much higher than those in either 2-SS or control. The HP-IgG level revealed an exclusively positive correlation with the serum PG II level and a negative correlation with the PG I/II ratio. Serum PG II levels and PG I/II ratios were associated with the positivity of HP-IgG antibodies. The age-specific seroprevalence rates of HP infection in SS patients compared with controls showed a high positivity in patients less than 49 years old, but no difference among the higher age groups because of increasing positive rates with advancing age in the control. The matched odds ratio with HP infection in all SS (1-SS and 2-SS) and in 1-SS were 2.33 (95% CI: 1.43–3.81) and 2.75 (95% CI: 1.50–5.05), respectively. However, the positive PG I/II ratio did not show a statistically significant odds ratio for SS. We conclude that SS patients have a highly positive association with HP infection and that atrophic gastritis with SS may occur as a result of HP infection.     

A pilot study to evaluate a new combination therapy for gastric ulcer: Helicobacter pylori eradication therapy followed by gastroprotective treatment with rebamipide

Background and Aim: Controversies remain over the need for antiulcer treatment following 1‐week eradication triple therapy for Helicobacter pylori‐positive peptic ulcers. The usefulness of combination therapy for gastric ulcers in Japanese patients, which consists of H. pylori eradication followed by gastroprotective therapy with rebamipide, was therefore evaluated. Methods: The study was conducted in 52 H. pylori‐positive patients with an endoscopically‐proven open gastric ulcer. All patients received 1‐week triple therapy (lansoprazole, amoxicillin and clarithromycin) followed by 7‐week rebamipide therapy. After completion of the combination therapy, all patients underwent evaluation of ulcer healing by endoscopy, gastric ulcer symptoms and H. pylori eradication by rapid urease test and ¹³C‐urea breath test. Results: The ulcer healing rates were 85.7% (36/42) at 8 weeks, 83.3% (30/36) in eradicated patients and 100% (6/6) in non‐eradicated patients. The overall gastrointestinal symptom‐free rate improved from 19.0% at baseline to 88.1% at 8 weeks. H. pylori was effectively eradicated in 85.7% (36/42) of patients. Conclusions: The results suggested that the combination therapy for open gastric ulcer was safe, well‐tolerated and effective. However, data from a double‐blind placebo‐controlled study is necessary to confirm these findings.     

Role of histamine H2 receptors in the mechanism of formation of experimental gastric ulcers induced in rats by various stressors

Dystrophic lesions of the gastric mucosa were observed to be formed and the pepsinogen content was reduced by 57% in the gastric mucosa of rats exposed to various experimental stressors (immobilization with electrical stimulation, immobilization at 6°C, trauma to or ligation of the pylorus). and the changes correlated with the degree of injury to the stomach. Pharmacological blockade of H2 receptors by cimetidine (100 moles/kg) and methiamide (410 moles/kg) largely prevented the formation of experimental ulcers and the decrease in the pepsinogen level. The results indicate that endogenous histamine participates in the mechanism of formation of dystrophic gastric lesions.Department of Pharmacology, Institute of Experimental Medicine, Academy of Medical Sciences of the USSR, Leningrad. (Presented by Academician of the Academy of Medical Sciences of the USSR S. V. Anichkov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 88, No. 8, pp. 151–153, August, 1979.     

Characterization of human pepsin I obtained from purified gastric pepsinogen I

Summary Immunochemical homogeneous human pepsinogen I-group (PgI) was purified by solid immunoadsorbent and by DEAE-chromatography from gastric mucosa. PgI contained five electrophoretic distinct bands at pH 8.2 but only four bands at pH 5.6. After acid activation human pepsin (PI) was separated from the inhibitory peptide by affinity chromatography using poly-L-lysine. Purified PgI contained 9–16% of the inhibitory peptide. The yield of PI was 64 to 85%. A 65% increase of specific activity was observed. PI demonstrated three bands in agar gel electrophoresis at pH 5.6. The pH range of PI was rather wide, showing two maxima at pH 2.0 and pH 3.0 with hemoglobin as substrate. Irreversible inactivation of PI was observed at pH 7.0 and at a temperature of 60° C. The K_m-value of PI was 0.170 mmol as determined with N-acetyl-L-phenyl-alanyl-L-3,5 diiodotyrosine. The specific activity was 9.6 IU/mg (hemoglobin substrate) and 0.032 IU/mg (dipeptide substrate). Porc pepsinogen (PPg) and its activated pepsin (PP) was used for comparison. PP showed identical elution patterns in affinity chromatography. In AEE PPg and PP demonstrated both two components at pH 5.6 with different electrophoretic mobilities. The pH optimum of PP was observed at pH 2.0. PP was slightly more sensitive in alkali and heat inactivation than human P. A higher K_m-value of PP of 0.082 mmol and higher specific activity as compared to human PI was observed.Supported in part by grants of the Deutsche Forschungsgemeinschaft     

Expression of pepsinogen I and II in human gastric carcinoma and precarcinous lesion

The antibodies to PgI and PgII are used to do the immunohistochemical study in human gastric carcinoma and precarcinous lesion. The results show that in embryo gastric mucosa the expression of PgI is positive while PgII is negative; in normal gastric mucosa both Pgs are positive expression; In precarcinous lesion of stomach the positive rate of both Pgs decrease strikingly, and decrease further to the lowest level when the gastric cancer occurs. It is suggested that PgI and PgII are the special marker of normal gastric mucosa. There is no obvious difference of PgI and PgII in the various types of gastric carcinoma. Both Pgs levels in advanced gastric cancer are higher than that in early stage. PgII expression is more in gastric cancer accompanied by lymphatic metastasis, which may be beneficial to the estimate of gastric carcinoma prognosis.     

Analysis of differentially expressed genes in human hepatocellular carcinoma using suppression subtractive hybridization.

The genetic basis of hepatocellular carcinoma (HCC) has not yet been fully understood. Although various methods have been developed to detect differentially expressed genes in malignant diseases, efficient analysis from clinical specimens is generally difficult to perform due to the requirement of a large amount of samples. In the present study, we analysed differentially expressed genes with a small amount of human HCC samples using suppression subtractive hybridization (SSH). Total RNA were obtained from the hepatitis C virus-associated HCC and adjacent non-HCC liver tissues. cDNA was synthesized using modified RT-PCR, and then tester cDNA was ligated with 2 different kinds of adaptors and hybridized with an excess amount of driver cDNA. Tester specific cDNA was obtained by suppression PCR and the final PCR product was subcloned and sequenced. We identified 7 known genes (focal adhesion kinase, deleted in colon cancer, guanine binding inhibitory protein alpha, glutamine synthetase, ornithine aminotransferase, M130, and pepsinogen C) and 2 previously unknown genes as being overexpressed in HCC, and 1 gene (decorin) as suppressed in HCC. Quantitative analysis of gene expression using quantitative RT-PCR demonstrated the differential expression of these genes in the original and other HCC samples. These findings demonstrated that it is possible to identify the previously unknown, differential gene expression from a small amount of clinical samples. Information about such alterations in gene expression could be useful for elucidating the genetic events in HCC pathogenesis, developing the new diagnostic markers, or determining novel therapeutic targets.     

Serum screening for detection of high-risk group for early-stage diffuse type gastric cancer in Japanese

Background and Aim: Serum screening systems are beneficial for gastric cancer mass surveys; however, the marker for diffuse type gastric cancer (DGC) is not defined. We attempted to define the high‐risk group for DGC by using serum markers of anti‐Helicobacter pylori antibody and pepsinogens (PG). Methods: Forty‐two patients in the early stage of DGC and 511 controls were enrolled. Fasting serum samples were collected, and anti‐H. pylori antibody and PG were evaluated. The risk for DGC was calculated. Results: The prevalence of DGC was higher in H. pylori‐positive patients (odds ratio [OR] = 4.3 in men, 9.6 in women). DGC prevalence was significantly higher in the PG1+ group in women (OR = 10.7); however, it was lower in the PG3+ group in both men and women. Patients with PG II ≥ 30 revealed a significantly higher risk for DGC. By combining factors, higher OR (OR = 12.5 in men, 42.7 in women) were obtained when we defined the risk group as H. pylori‐positive, PG‐negative, and having PG II ≥ 30. Conclusion: The risk group for DGC can be defined by evaluating ordinary serum gastritis markers.     

Application of serum pepsinogen and carbohydrate antigen 72-4 (CA72-4) combined with gastrin-17 (G-17) detection in the screening,diagnosis, and evaluation of early gastric cancer

BackgroundGastric cancer is a common malignant tumor. The aim of the present study was to analyze the application value of serum pepsinogen (PG), carbohydrate antigen 72-4 (CA72-4), and gastrin-17 (G-17) detection in the screening, diagnosis, and evaluation of early gastric cancer.MethodsIn total, 122 patients with gastric cancer treated in our hospital from January 2018 to January 2021 were selected as the gastric cancer group and subdivided into the early gastric cancer (group A) and advanced gastric cancer (group B) groups. Sixty-five patients with benign gastric disease treated in the same hospital during the same period were selected as the control group, and 122 healthy people who underwent physical examination during the same period were allocated to the control group. The differences in the levels of G-17, PGI, PGII, PGI/PGII, and CA72-4 were compared; receiver-operating characteristic curves were drawn; and the efficacy of different factors in the diagnosis of early gastric cancer was calculated.ResultsG-17, PGI, and PGI/PGII levels in the gastric cancer group were significantly lower than those in the healthy group, and CA72-4 was significantly higher than that in the healthy group (P<0.05), but there was no significant difference in PGII between the 2 groups (P>0.05). G-17, PGI, and PGI/PGII levels in groups A and B were significantly lower than those in the control group. CA72-4 in groups A and B was significantly higher than that of the control group, and was highest in group B (P<0.05). The areas under the curve (AUC) of G-17, PGI, PGI/PGII, and CA72-4 were 0.671, 0.726, 0.769, and 0.602, respectively, and the AUC of combined detection was 0.883, which was significantly higher than that of single detection.ConclusionsSerum PG, CA72-4 combined with G-17 detection has high sensitivity and specificity in the screening and diagnosis of early gastric cancer, and has high clinical application value.     

血清PG、G-17联合CA72-4和13C UBT在早期胃癌的诊断价值

目的 探讨血清胃蛋白酶原(PG)、胃泌素17(G-17)在胃癌的水平变化情况,在此基础之上联合糖类抗原72-4(CA72-4)以及13C尿素呼气试验(13C UBT)的检测在早期胃癌的诊断意义.方法 使用酶联免疫吸附试验(ELISA)检测健康人(对照组)、萎缩性胃炎组和胃癌组血清PGⅠ、PGⅡ、G-17的水平,先比较以上3种指标的变化情况;后根据PGⅠ和G-17将胃癌组分为A、B、C、D组后,对4组受检者,采用13C呼气试验检测幽门螺杆菌感染情况,利用肿瘤标记物检测结果统计CA72-4的水平情况.结果 PGⅠ血清水平和PG Ⅰ/PGⅡ比值在对照组、萎缩性胃炎组以及胃癌组中逐渐下降,差异有统计学意义(P＜0.05);G-17血清水平在对照组、萎缩性胃炎组以及胃癌组中逐步增加,3组之间水平差异有统计学意义(P＜0.05);A～D 4组间早期胃癌率比值中,B组的早期胃癌阳性率最高,差异有统计学意义(P＜0.05);4组中比较”C UBT和CA72-4水平在早期胃癌的阳性率的情况,B组13C阳性率和CA72-4水平高于ACD组,差异均有统计学意义(P＜0.05).并且B组CA72-4水平在早期胃癌和进展期胃癌差异上更加明显(P＜0.01).结论 血清PG Ⅰ降低和G-17水平升高联合CA72-4高水平和”C UBT阳性对于胃癌的诊断具有重要的预警价值.