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.

Estrogen Regulates Duodenal Calcium Absorption Through Differential Role of Estrogen Receptor on Calcium Transport Proteins.

BACKGROUND AND AIMS: Intestinal calcium absorption from the diet plays important role in maintaining calcium homeostasis in the body. Estrogen exerts wide physiological and pathological effects in the human. Previous studies have shown that estrogen is involved in the intestinal calcium absorption. In this study, we made investigation on the mechanism of estrogen action on duodenal calcium absorption. METHODS: The experiments were performed in mice, human, and human duodenal epithelial cells, SCBN cells. Murine duodenal calcium absorption was measured by using single pass perfusion of the duodenum in vivo. The calcium absorption of SCBN cells was evaluated by calcium imaging system. The expression of calcium transport proteins, transient receptor potential cation channel (TRPV6) and plasma membrane calcium pump (PMCA1b), in the duodenum or SCBN cells were analyzed by western blot. RESULTS: The duodenal calcium absorption in ovariectomized mice was significantly decreased, compared with control female mice, which returned to control level after 17ß-estradiol replacement treatment. Estrogen regulated the expressions of TRPV6 and PMCA1b in murine and human duodenal mucosae and SCBN cells. The further results from SCBN cells showed that 17ß-estradiol regulated calcium influx through the respective effects of estrogen receptor (ER) ɑ and ß on TRPV6 and PMCA1b. CONCLUSION: Estrogen regulates duodenal calcium absorption through differential role of ERɑ and ERß on duodenal epithelial cellular TRPV6 and PMCA1b. The study further elucidates the mechanism of estrogen on the regulation of intestinal calcium absorption.

Helicobacter pylori infection downregulates duodenal CFTR and SLC26A6 expressions through TGFß signaling pathway.

BACKGROUND: The pathogenesis of Helicobacter pylori (H. pylori) infection-induced duodenal ulcer remains to be elucidated. Duodenal mucosal bicarbonate secretion is the most important protective factor against acid-induced mucosal injury. We previously revealed that H. pylori infection downregulated the expression and functional activity of duodenal mucosal cystic fibrosis transmembrane conductance regulator (CFTR) and solute linked carrier 26 gene family A6 (SLC26A6) which are the two key duodenal mucosal epithelial cellular bicarbonate transporters to mediate duodenal bicarbonate secretion. In this study, we investigated the mechanism of H. pylori infection-induced duodenal CFTR and SLC26A6 expression downregulation. RESULTS: We found that H. pylori infection induced the increase of serum transforming growth factor ß (TGFß) level and duodenal mucosal TGFß expression and the decrease of duodenal mucosal CFTR and SLC26A6 expressions in C57 BL/6 mice. The results from the experiments of human duodenal epithelial cells (SCBN) showed that H. pylori increased TGFß production and decreased CFTR and SLC26A6 expressions in SCBN cells. TGFß inhibitor SB431542 reversed the H. pylori-induced CFTR and SLC26A6 expression decreases. The further results showed that TGFß directly decreased CFTR and SLC26A6 expressions in SCBN cells. TGFß induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and P38 MAPK inhibitor SB203580 reversed the TGFß-induced CFTR and SLC26A6 expression decreases. CONCLUSIONS: H. pylori infection downregulates duodenal epithelial cellular CFTR and SLC26A6 expressions through TGFß-mediated P38 MAPK signaling pathway, which contributes to further elucidating the pathogenesis of H. pylori-associated duodenal ulcer.

Na+/H+ exchanger 1, Na+/Ca2+ exchanger 1 and calmodulin complex regulates interleukin 6-mediated cellular behavior of human hepatocellular carcinoma.

Interleukin 6 (IL6) is a key cytokine involved in the development and progression of inflammation-associated hepatocellular carcinoma (HCC). However, the mechanisms of IL6 action on HCC remain largely unknown. Proton and Ca(2+) are two intracellular messenger ions, which are believed to play a central role in tumorigenesis and tumor progression. In this study, we found that IL6 stimulation markedly increased intracellualr pH recovery rates of human HCC cells, Huh7 and HepG2, after NH4Cl acidification, and the NH4Cl acidification induced transient intracellular Ca(2+) increases in the HCC cells. The inhibition of Na(+)/H(+) exchanger 1 (NHE1), Na(+)/Ca(2+) exchanger 1 (NCX1) and calmodulin (CaM) inhibited the IL6 stimulation-induced intracellular pH recovery increases and NH4Cl acidification-induced intracellular Ca(2+) increases. IL6 stimulation also induced the structural interaction of NHE1, NCX1 and CaM proteins. The protein expression levels of NHE1, NCX1 and CaM in native human HCC tissues were markedly higher than those in normal liver tissues. IL6 upregulated the expressions of NHE1, NCX1 and CaM in Huh7 and HepG2 cells. NHE1, NCX1 and CaM mediated the promotion of IL6 on the proliferation, migration and invasion of Huh7 and HepG2 cells and the growth of HCC in nude mice. In conclusion, IL6 activates the functional activity of NHE1 and induces the functional and structural interaction of NHE1, NCX1 and CaM. The interaction of NHE1, NCX1 and CaM mediates the effects of IL6 on human HCC.

Oestrogen upregulates the expression levels and functional activities of duodenal mucosal CFTR and SLC26A6.

NEW FINDINGS: What is the central question of this study? Duodenal ulcer is a common disease. A sex-based difference in the incidence of duodenal ulcer has long been observed clinically, but the cause is unclear. What is the main finding and its importance? Duodenal mucosal bicarbonate secretion is the most important protective factor in duodenal mucosa against acid-induced damage. The cystic fibrosis transmembrane conductance regulator (CFTR) and the solute-linked carrier 26 gene family A6 (SLC26A6) are two key bicarbonate transport proteins that mediate duodenal mucosal bicarbonate secretion. We demonstrate that endogenous oestrogen upregulates the expression levels and functional activities of duodenal mucosal CFTR and SLC26A6, which contributes to the sex difference in the prevalence of duodenal ulcer. The incidence of duodenal ulcer is markedly lower in women than men, but the cause of the sex difference is not clear. The cystic fibrosis transmembrane conductance regulator (CFTR) and the solute-linked carrier 26 gene family A6 (SLC26A6) are two key bicarbonate transport proteins that mediate duodenal mucosal bicarbonate secretion, which is an important protective factor against acid-induced duodenal injury. The aim of this study was to investigate the effect of oestrogen on the expressions and functional activities of CFTR and SLC26A6 in duodenal mucosa. We found that the expression levels of duodenal CFTR and SLC26A6 were markedly higher in young (20- to 30-year-old) women than in young men and old (60- to 70-year-old) women and men. The expression levels of CFTR and SLC26A6 in young women were markedly higher in preovulatory phases than in premenstrual phases, which was consistent with the changes of serum estradiol concentrations. Further results showed that duodenal CFTR and SLC26A6 expression levels in female mice were markedly decreased after ovariectomy, and supplementation with estradiol reversed the changes in CFTR and SLC26A6. 17ß-Estradiol increased CFTR and SLC26A6 expression levels of human duodenocytes in experiments in vitro. Functional experiments showed that basal and forskolin- and prostaglandin E2 -stimulated duodenal bicarbonate secretion in ovariectomized mice was markedly decreased and, likewise, supplementation with 17ß-estradiol reversed the changes. In conclusion, endogenous oestrogen upregulates the expressions and functional activities of CFTR and SLC26A6 in duodenal mucosa, which could contribute to protection of the duodenum and explain the sex difference in the prevalence of duodenal ulcer.

Effects of Helicobacter pylori Infection on the Expressions and Functional Activities of Human Duodenal Mucosal Bicarbonate Transport Proteins.

BACKGROUND: The mechanisms for Helicobacter pylori (H. pylori)-induced duodenal ulcerogenesis are not fully understood. In this study, we investigated the effects of H. pylori infection on the expressions and functional activities of human duodenal mucosal bicarbonate transport proteins and hope to further clarify the pathogenesis of H. pylori-associated duodenal ulcer. MATERIALS AND METHODS: The experiments were performed in the patients with H. pylori-associated duodenal ulcers, H. pylori-associated chronic gastritis, and H. pylori-negative healthy subjects. Duodenal mucosal bicarbonate secretion was measured by Ussing Chamber technology. RESULTS: The expressions of duodenal mucosal bicarbonate transport proteins, CFTR (cystic fibrosis transmembrane conductance regulator) and SLC26A6 (solute-linked carrier 26 gene A6), in the patients with H. pylori-associated duodenal ulcers were markedly lower than those in healthy controls. Basal and both forskolin- and prostaglandin E2 -stimulated duodenal mucosal bicarbonate secretions in the patients with H. pylori-associated duodenal ulcers were also lower than those in healthy controls. After anti-H. pylori treatment for H. pylori-associated duodenal ulcers, duodenal mucosal bicarbonate secretion and CFTR and SLC26A6 expressions in H. pylori-eradicated patients recovered to levels comparable to healthy controls, but those were found to be not significantly altered in non-H. pylori-eradicated patients. The further results showed that decreases in the H. pylori-induced CFTR and SLC26A6 expression were related to the severity and virulent factors of H. pylori infection. CONCLUSION: H. pylori infection impairs the expressions and functional activities of duodenal mucosal bicarbonate transport proteins, CFTR and SLC26A6, which contributes to the development of duodenal ulcer.

The P2Y2 nucleotide receptor mediates the proliferation and migration of human hepatocellular carcinoma cells induced by ATP.

ATP is an abundant biochemical component of the tumor microenvironment and a physiologic ligand for the P2Y2 nucleotide receptor (P2Y2R). In this study, we investigated the effect of ATP on the cellular behavior of human hepatocellular carcinoma (HCC) cells and the role of P2Y2R in ATP action and aimed to find a new therapeutic target against HCC. The experiments were performed in native isolated human HCC cells, normal hepatocytes, human HCC cell lines, and nude mice. We found that the mRNA and protein expression levels of P2Y2R in native human HCC cells and the human HCC cell lines HepG2 and BEL-7404 were enhanced markedly compared with human normal hepatocytes and the normal hepatocyte line LO2, respectively. ATP induced intracellular Ca(2+) increases in HCC cells and promoted the proliferation and migration of HCC cells and the growth of HCC in nude mice. The P2Y receptor antagonist suramin, P2Y2R-specific shRNA, the store-operated calcium channel inhibitors 2-aminoethoxydiphenyl borate (2-APB) and 1-(ß-3-(4-methoxy-phenyl) propoxyl-4-methoxyphenethyl)1H-imidazole-hydrochloride (SKF96365), and stromal interaction molecule (STIM1)-specific shRNA inhibited the action of ATP on HCC cells. In conclusion, P2Y2R mediated the action of ATP on the cellular behavior of HCC cells through store-operated calcium channel-mediated Ca(2+) signaling, and targeting P2Y2R may be a promising therapeutic strategy against human HCC.

SLC26A9 promotes colorectal tumorigenesis by modulating Wnt/ß-catenin signaling.

Solute carrier family 26 member 9 (SLC26A9) is a member of the Slc26a family of multifunctional anion transporters that functions as a Cl- channel in parietal cells during acid secretion. We explored the role of SLC26A9 in colorectal cancer (CRC) and its related mechanisms through clinical samples from CRC patients, CRC cell lines and mouse models. We observed that SLC26A9 was expressed at low levels in the cytoplasm of adjacent tissues, polyps and adenomas but was significantly increased in colorectal adenocarcinoma. Moreover, increased levels of SLC26A9 were associated with a high risk of disease and poor prognosis. In addition, downregulation of SLC26A9 in CRC cells induced cell cycle arrest and apoptosis but inhibited cell proliferation and xenograft tumor growth both in vitro and in vivo. Mechanistic analysis revealed that SLC26A9 was colocalized with ß-catenin in the nucleus of CRC cells. The translocation of these two proteins from the cytoplasm to the nucleus reflected the activation of Wnt/ß-catenin signaling, and promoted the transcription of downstream target proteins, including CyclinD1, c-Myc and Snail, but inhibited the expression of cytochrome C (Cyt-c), cleaved Caspase9, cleaved Caspase3 and apoptosis-inducing factor (AIF). CRC is accompanied by alteration of epithelial mesenchymal transition (EMT) markers. Meanwhile, further studies showed that in SW48 cells, overexpressing SLC26A9 was cocultured with the ß-catenin inhibitor XAV-939, ß-catenin was downregulated, and EMT was reversed. Our study demonstrated SLC26A9 may be responsible for alterations in the proliferative ability and aggressive potential of CRC by regulating the Wnt/ß-catenin signaling pathway.

Role of lactate and lactate metabolism in liver diseases (Review).

Lactate is a byproduct of glycolysis, and before the Warburg effect was revealed (in which glucose can be fermented in the presence of oxygen to produce lactate) it was considered a metabolic waste product. At present, lactate is not only recognized as a metabolic substrate that provides energy, but also as a signaling molecule that regulates cellular functions under pathophysiological conditions. Lactylation, a post­translational modification, is involved in the development of various diseases, including inflammation and tumors. Liver disease is a major health challenge worldwide. In normal liver, there is a net lactate uptake caused by gluconeogenesis, exhibiting a higher net lactate clearance rate compared with any other organ. Therefore, abnormalities of lactate and lactate metabolism lead to the development of liver disease, and lactate and lactate metabolism­related genes can be used for predicting the prognosis of liver disease. Targeting lactate production, regulating lactate transport and modulating lactylation may be potential treatment approaches for liver disease. However, currently there is not a systematic review that summarizes the role of lactate and lactate metabolism in liver diseases. In the present review, the role of lactate and lactate metabolism in liver diseases including liver fibrosis, non­alcoholic fatty liver disease, acute liver failure and hepatocellular carcinoma was summarized with the aim to provide insights for future research.

Pathophysiological role of ion channels and transporters in hepatocellular carcinoma.

The incidence of hepatocellular carcinoma (HCC) has continued to increase annually worldwide, and HCC has become a common cause of cancer-related death. Despite great progress in understanding the molecular mechanisms underlying HCC development, the treatment of HCC remains a considerable challenge. Thus, the survival and prognosis of HCC patients remain extremely poor. In recent years, the role of ion channels in the pathogenesis of diseases has become a hot topic. In normal liver tissue, ion channels and transporters maintain water and electrolyte balance and acid‒base homeostasis. However, dysfunction of these ion channels and transporters can lead to the development and progression of HCC, and thus these ion channels and transporters are expected to become new therapeutic targets. In this review, ion channels and transporters associated with HCC are reviewed, and potential targets for new and effective therapies are proposed.

[Effects of weile powder on bicarbonate transporters CFTR SLC26A3 and SLC26A6 in gastric ulcers of rats].

OBJECTIVE: To investigate the effects of Weile Powder (WLP) on bicarbonate transporters in rats with gastric ulcers, and to probe its functional mechanisms. METHODS: The 48 SD rats were randomly divided into the normal control group, the model group, the low dose WLP group (at the daily dose of 0.075 g/mL), the middle dose WLP group (at the daily dose of 0.150 g/mL), the high dose WLP group (at the daily dose of 0.030 g/mL), and the ranitidine group (at the daily dose of 0.030 g/mL), 8 in each group. The gastric ulcer rat model was prepared by the glacial acetic acid cauterization method. Rats in each medication group were administered from the 2nd day of modeling. Rats were sacrificed after 14-day successive medication. The protein was extracted from the ulcer tissue. The protein expressions of solute carrier26A3 (SLC26A3)and solute carrier26A6 (SLC26A6) were detected using Western blot. The gastric ulcer and its peripheral tissue were sectioned. The changes of cystic fibrosis transmembrane conductance regulator (CFTR) were measured by immunofluorescence. RESULTS: Compared with the model control group, the expression levels of SLC26A3 increased in the high dose WLP group and the ranitidine group with statistical difference (P < 0.05). The expression levels of SLC26A6 increased in the high and middle dose WLP groups and the ranitidine group with statistical difference (P < 0.05). The expression level of CFTR also obviously increased in the high and middle dose WLP groups (P < 0.01). CONCLUSION: WLP could elevate the expression levels of SLC26A6, SLC26A3, and CFTR, increase the secretion of bicarbonate, thus protecting the gastric mucosa.

Digestive system infection by SARS­CoV­2: Entry mechanism, clinical symptoms and expression of major receptors (Review).

Besides causing severe acute respiratory syndrome (SARS), SARS­coronavirus 2 (SARS­CoV­2) also harms the digestive system. Given the appearance of numerous cases of SARS­CoV­2, it has been demonstrated that SARS­CoV­2 is able to harm target organs such as the gastrointestinal tract, liver and pancreas, and either worsen the condition of patients with basic digestive illnesses or make their prognosis poor. According to several previously published studies, angiotensin­converting enzyme II (ACE2) and transmembrane serine protease II (TMPRSS2) are expressed either singly or in combination in the digestive system and in other regions of the human body. In order to change the viral conformation, create a fusion hole and release viral RNA into the host cell for replication and transcription, SARS­CoV­2 is capable of binding to these two proteins through the spike protein on its surface. As a result, the body experiences an immune reaction and an inflammatory reaction, which may lead to nausea, diarrhea, abdominal pain and even gastrointestinal bleeding, elevated levels of liver enzymes, acute liver injury, pancreatitis and other serious lesions. In order to provide possible strategies for the clinical diagnosis and treatment of digestive system diseases during the COVID­19 pandemic, the molecular structure of SARS­CoV­2 and the mechanism via which SARS­CoV­2 enters the human body through ACE2 and TMPRSS2 were discussed in the present review, and the clinical manifestations of SARS­CoV­2 infection in the digestive system were also summarized. Finally, the expression characteristics of ACE2 and TMPRSS2 in the main target organs of the digestive system were described.

The S100 calcium-binding protein A6 plays a crucial role in hepatic steatosis by mediating lipophagy.

BACKGROUND: S100 calcium-binding protein A6 (S100A6) is a calcium-binding protein that is involved in a variety of cellular processes, such as proliferation, apoptosis, and the cellular response to various stress stimuli. However, its role in NAFLD and associated metabolic diseases remains uncertain. METHODS AND RESULTS: In this study, we revealed a new function and mechanism of S100A6 in NAFLD. S100A6 expression was upregulated in human and mouse livers with hepatic steatosis, and the depletion of hepatic S100A6 remarkably inhibited lipid accumulation, insulin resistance, inflammation, and obesity in a high-fat, high-cholesterol (HFHC) diet-induced murine hepatic steatosis model. In vitro mechanistic investigations showed that the depletion of S100A6 in hepatocytes restored lipophagy, suggesting S100A6 inhibition could alleviate HFHC-induced NAFLD. Moreover, S100A6 liver-specific ablation mediated by AAV9 alleviated NAFLD in obese mice. CONCLUSIONS: Our study demonstrates that S100A6 functions as a positive regulator of NAFLD, targeting the S100A6-lipophagy axis may be a promising treatment option for NAFLD and associated metabolic diseases.

Novel roles of karyopherin subunit alpha 2 in hepatocellular carcinoma.

Hepatocellular carcinoma is the most common type of liver cancer and associated with a high fatality rate. This disease poses a major threat to human health worldwide. A considerable number of genetic and epigenetic factors are involved in the development of hepatocellular carcinoma. However, the molecular mechanism underlying the progression of hepatocellular carcinoma remains unclear. Karyopherin subunit alpha 2 (KPNA2), also termed importin α1, is a member of the nuclear transporter family. In recent years, KPNA2 has been gradually linked to the nuclear transport pathway for a variety of tumor-associated proteins. Furthermore, it promotes tumor development by participating in various pathophysiological processes such as cell proliferation, apoptosis, immune response, and viral infection. In hepatocellular carcinoma, it has been found that KPNA2 expression is significantly higher in liver cancer tissues versus paracancerous tissues. Moreover, it has been identified as a marker of poor prognosis and early recurrence in patients with hepatocellular carcinoma. Nevertheless, the role of KPNA2 in the development of hepatocellular carcinoma remains to be determined. This review summarizes the current knowledge on the pathogenesis and role of KPNA2 in hepatocellular carcinoma, and provides new directions and strategies for the diagnosis, treatment, and prediction of prognosis of this disease.

Expression and functional role of vacuolar H(+)-ATPase in human hepatocellular carcinoma.

Tumor cells often exist in a hypoxic microenvironment, which produces acidic metabolites. To survive in this harsh environment, tumor cells must exhibit a dynamic cytosolic pH regulatory system. Vacuolar H(+)-adenosine triphosphatase (V-ATPase) is considered to play an important role in the regulation of the acidic microenvironment of some tumors. In this study, we made an investigation on the expression and functional role of V-ATPase in native human hepatocellular carcinoma (HCC). The results showed that the messenger RNA and protein expression levels of V-ATPase subunit ATP6L in native human HCC tissues were markedly increased, compared with normal liver tissues. Immunohistochemical analysis further confirmed the enhanced expression of V-ATPase ATP6L in human HCC cells and revealed that V-ATPase ATP6L was distributed in the cytoplasm and plasma membrane of HCC cells. The results from immunofluorescence and biotinylation of cell surface protein showed that V-ATPase ATP6L was conspicuously located in the plasma membrane of human HCC cells. Bafilomycin A1, a specific V-ATPase inhibitor, markedly slowed the intracellular pH (pHi) recovery after acid load in human HCC cells and retarded the growth of human HCC in orthotopic xenograft model. These results demonstrated that V-ATPase is up-regulated in human HCC and involved in the regulation of pHi of human HCC cells. The inhibition of V-ATPase can effectively retard the growth of HCC, indicating that V-ATPase may play an important role in the development and progression of human HCC, and targeting V-ATPase may be a promising therapeutic strategy against human HCC.

Estrogen potentiates prostaglandin E2-stimulated duodenal mucosal HCO3⁻ secretion in mice.

The cause of lower prevalence of duodenal ulcer in young women compared with men is largely unknown. We recently found that sex difference in duodenal mucosal HCO3⁻ secretion existed in humans and mice, but the mechanisms are not clear. Prostaglandin E2 (PGE2) is an important endogenous mediator that plays an important role in the regulation of duodenal HCO3⁻ secretion. Therefore, in the present study, we investigated the effect of estrogen on PGE2-stimulated duodenal HCO3⁻ secretion and the underlying mechanisms. The results showed that 17ß-estradiol at the physiological concentration (1 nM) had no significant effects on duodenal mucosal HCO3⁻ secretion or short-circuit current (I(sc)) in mice. However, the pretreatment of 17ß-estradiol (1 nM) markedly potentiated PGE2-stimulated duodenal HCO3⁻ secretion and I(sc) (P < 0.01 and P < 0.05). Global estrogen receptor (ER) antagonist ICI-182,780 and ERα-specific antagonist MPP, but not the ERß-specific antagonist PHTPP, abolished estrogen-potentiated PGE2-stimulated duodenal HCO3⁻ secretion and I(sc). 17ß-Estradiol and PGE2 additively increased phosphatidylinositol 3-kinase (PI3K) activity and Akt phosphorylation. Wortmannin, a specific PI3K inhibitor, inhibited estrogen-potentiated PGE2-stimulated duodenal HCO3⁻ secretion and I(sc). In conclusion, estrogen at the physiological concentration potentiates PGE2-stimulated duodenal mucosal HCO3⁻ secretion through the activation of ERα and the PI3K-dependent mechanism, which may contribute to the sex difference in duodenal mucosal HCO3⁻ secretion and the lower prevalence of duodenal ulcer in young women.

Estrogen regulation of duodenal bicarbonate secretion and sex-specific protection of human duodenum.

BACKGROUND & AIMS: The reason that women have a lower prevalence of duodenal ulcer is not clear. We investigated whether estrogen regulates human duodenal bicarbonate secretion (DBS) and whether this process accounts for sex differences in the prevalence of duodenal ulcer. METHODS: We performed an epidemiologic study to correlate duodenal ulcer prevalence with sex and age. Proximal DBS was measured from healthy subjects. Estrogen-receptor expression was examined in human duodenal mucosa by immunoblot and immunohistochemical analyses. RESULTS: Among women, the prevalence of duodenal ulcer was significantly lower than among men. The reduced prevalence was greatest among premenopausal women (20-49 y), who were 3.91- to 5.09-fold less likely to develop duodenal ulcers than age-matched men; the difference was reduced to 1.32-fold or less among subjects aged 60 years or older. Premenopausal (20-29 y), but not postmenopausal (60-69 y), women had significantly higher basal and acid-stimulated DBS than the age-matched men. Basal and acid-stimulated DBS in premenopausal women (20-29 y) were significantly higher than in postmenopausal women (60-69 y), whereas there were no significant differences in basal or acid-stimulated DBS between men who were aged 20-29 years or 60-69 years. Serum levels of estradiol changed in parallel with basal and acid-stimulated DBS during the physiological menstrual cycle in premenopausal women. 17ß-estradiol-stimulated DBS was independent of age or sex. Estrogen receptors α and ß were detected on plasma membranes and in the cytosol of human duodenal epithelial cells. CONCLUSIONS: Estrogen regulates human DBS, which could reduce the risk for duodenal ulcer in women and contribute to sex differences in the prevalence of duodenal ulcer.

Pathology and physiology of acid­sensitive ion channels in the digestive system (Review).

As a major proton­gated cation channel, acid­sensitive ion channels (ASICs) can perceive large extracellular pH changes. ASICs play an important role in the occurrence and development of diseases of various organs and tissues including in the heart, brain, and gastrointestinal tract, as well as in tumor proliferation, invasion, and metastasis in acidosis and regulation of an acidic microenvironment. The permeability of ASICs to sodium and calcium ions is the basis of their physiological and pathological roles in the body. This review summarizes the physiological and pathological mechanisms of ASICs in digestive system diseases, which plays an important role in the early diagnosis, treatment, and prognosis of digestive system diseases related to ASIC expression.

The source of the fat significantly affects the results of high-fat diet intervention.

High-fat diet (HFD) is widely used in animal models of many diseases, it helps to understand the pathogenic mechanism of related diseases. Several dietary fats were commonly used in HFD, such as corn oil, peanut oil, soybean oil, sunflower oil, and lard. However, it was reported that different dietary fat could have completely different effects on physiological indicators and the gut microbiome, and the sources of dietary fat used in high-fat diet research have not been comprehensively compared. In this research, we conduct comparative experiments on various sources of dietary fats to test their different effects during the high-fat diet intervention. We investigated the effects of twelve common dietary fats in high-fat diet intervention of mice, body/liver weight changes, four blood lipid indices, and gut microbiome were analyzed. Our results showed that the source of dietary fat used in high-fat diet significantly affects the changes of body/liver weight and triglyceride (TRIG) in the blood. Furthermore, the intervention of canola oil increased the alpha diversity of gut microbiota, and lard has decreased diversity compared with the control group. The composition of saturated fatty acid (SFA) in fat has the most significant effects on the gut microbiome. All dietary fats treatments have an increasing Firmicutes abundance and a reduced Bacteroidetes abundance in gut microbiome, while the canola oil has a slight variation compared to other intervention groups, and the lard group has the largest changes. This study showed that different types of dietary fat have different effects on the body indicators and intestinal microbiota of mice, and canola oil produced less disturbance than other types of dietary fats in high-fat diet.

APOBEC3B: Future direction of liver cancer research.

Liver cancer is one of the most common cancers in the world, and the rate of liver cancer is high due to the of its illness. The main risk factor for liver cancer is infection with the hepatitis B virus (HBV), but a considerable number of genetic and epigenetic factors are also directly or indirectly involved in the underlying pathogenesis of liver cancer. In particular, the apolipoprotein B mRNA editing enzyme, catalytic peptide-like protein (APOBEC) family (DNA or mRNA editor family), which has been the focus of virology research for more than a decade, has been found to play a significant role in the occurrence and development of various cancers, providing a new direction for the research of liver cancer. APOBEC3B is a cytosine deaminase that controls a variety of biological processes, such as protein expression, innate immunity, and embryonic development, by participating in the process of cytidine deamination to uridine in DNA and RNA. In humans, APOBEC3B has long been known as a DNA editor for limiting viral replication and transcription. APOBEC3B is widely expressed at low levels in a variety of normal tissues and organs, but it is significantly upregulated in different types of tumor tissues and tumor lines. Thus, APOBEC3B has received increasing attention in various cancers, but the role of APOBEC3B in the occurrence and development of liver cancer due to infection with HBV remains unclear. This review provides a brief introduction to the pathogenesis of hepatocellular carcinoma induced by HBV, and it further explores the latest results of APOBEC3B research in the development of HBV and liver cancer, thereby providing new directions and strategies for the treatment and prevention of liver cancer.