Tag: Hong Kong

Research led by the School of Chinese Medicine at Hong Kong Baptist University (HKBU) has identified cryptotanshinone, a compound extracted from the Chinese herbal medicine Salvia miltiorrhiza, with the potential for the treatment and prevention of gastric cancer associated with bile reflux. The researchers unveiled the mechanism of how bile reflux induces gastritis and gastric cancer. They explained that refluxed bile acids (BAs) lead to the proliferation of pro-inflammation bacteria that promote gastric carcinogenesis, the formation of cancer.

The research findings have been published in the international scientific journal Advanced Science.

Role of bile reflux in gastric cancer unclear

Bile, secreted by the liver, is stored in the gallbladder and is released to the duodenum to help digest fat. When the pylorus connecting the stomach and the duodenum is damaged or fails to work properly, bile in the duodenum can enter the stomach, causing gastritis. People with stomach surgery complications, peptic ulcers or gallbladder removal surgery have higher risks of bile reflux. However, the mechanism of how bile reflux induces gastric carcinogenesis remains unclear.

Professor Jia Wei, Associate Dean (International Collaboration) of Chinese Medicine and Cheung On Tak Endowed Professor in Chinese Medicine at HKBU, in collaboration with researchers from Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, conducted a study on how bile reflux induces gastric carcinogenesis, and looked for new prevention and therapeutic approaches.

Professor Jia said: “We unveiled for the first time the underlying mechanism by which bile reflux promoted the development of gastric carcinogenesis. It offers important clinical insights on the development of novel prevention and therapeutic approaches for the disease. Based on the newly discovered mechanism, we identified cryptotanshinone as a potential Chinese medicine-based pharmaceutic agent for the prevention and treatment of gastric carcinogenesis due to bile reflux.”

Bile reflux alters gastric environment

The research team analysed the gastric juice samples of 50 patients with bile reflux gastritis (BRG group), 50 patients with gastric cancer (GC group) and 45 subjects in the control group using chromatography and mass spectrometry techniques. It was found that the amounts of BAs, the major component of bile, in the gastric juice samples of BRG and GC groups are significantly higher than in the control group. Furthermore, the acidities of gastric juice samples of the BRG group (pH value about 3.5) and the GC group (pH value about 4) are drastically lower than in the control group (pH value about 2).

The phenomenon is explained by the fact that BAs are weak acids compared with strong gastric acid, and their influx into the stomach changed the gastric environment by upsetting the normal acid-base balance of the gastric juice. Further investigation found that a specific type of BA, called taurodeoxycholic acid (TDCA), showed a strong positive correlation with pH value of gastric juice samples of the BRG and GC groups.

Previous studies showed that bile reflux is closely related to chronic gastric inflammation and gastric carcinogenesis. The researchers thus examined the concentrations of lipopolysaccharide (LPS), a pro-inflammation cytokine, in the gastric juice of the 145 subjects above, and found that the BRG and GC groups have LPS concentrations significantly higher than those of the control group.

Change in microbiota associates with gastric carcinogenesis

As LPS is produced and found in the outer membrane of certain kinds of bacteria, the researchers applied gene sequencing and other techniques and confirmed that LPS-producing bacteria are significantly more abundant in the gastric juice of BRG and CG groups compared to the control group. Among these LPS-producing bacteria, a species called P. melaninogenica had the highest relative abundance.

From these experimental results, it is suggested that bile reflux induces significant changes in the gastric environment, alters the gastric microbiota, and results in the development of gastritis and gastric carcinogenesis. The hypothesis was tested with a series of in vitro and in vivo experiments in mice, which confirmed that application of TDCA and LPS promotes gastric epithelial cell proliferation, and induces gastric inflammation. Cellular and molecular analysis revealed that P. melaninogenica promoted gastric inflammation in mice by activating the IL-6/JAK1/STAT3 pathway, a chain of interactions between proteins in a cell involved in processes such as immunity, cell division, cell death, and tumour formation.

Cryptotanshinone as potential pharmaceutic agent

After unveiling the mechanism of bile reflux-induced gastric cancer, the researchers turned to explore a corresponding preventive and therapeutic approach. They focused on cryptotanshinone, a bioactive compound isolated from the roots of Salvia miltiorrhiza, which is a Chinese herbal medicine that facilitates blood circulation with an anti-inflammatory effect. Cryptotanshinone is also known as an inhibitor of the STAT3 signaling pathway in cells.

The researchers tested the effects of cryptotanshinone with a bile reflux mouse model developed through surgery. In a group of eight mice without application of cryptotanshinone, three mice developed gastric lesions 50 weeks after surgery. However, in another group of six mice injected with cryptotanshinone, no obvious gastric lesions were observed. The results suggested that cryptotanshinone has abolished the effects of TDCA and LPS in activating the IL-6/JAK1/STAT3 pathway.

“Based on the research findings, it can be concluded that cryptotanshinone is a potential Chinese medicine-based pharmaceutic agent for the prevention and treatment of gastric carcinogenesis due to bile reflux. It provides an alternative strategy for the development of medication which targets on the newly discovered mechanism of how bile reflux induces gastric carcinogenesis,” said Professor Jia.

A study led by Hong Kong Baptist University (HKBU) has revealed the association between rapidly fading antibody levels in some recovered COVID-19 patients and a high plasma concentration of a metabolite called glycylproline (gly-pro) and its producing enzyme.

The researchers also found that the application of an inhibiting agent can counteract the activities of gly-pro and its producing enzyme, and this helped to maintain COVID-19 antibody levels in a mouse model. The findings offer important insights that could aid the development of novel therapeutic and vaccination strategies against the virus.

The research results have been published in the Proceedings of the National Academy of Sciences (PNAS), a renowned international scientific journal.

Antibody levels drop in some recovered COVID-19 patients

The levels of COVID-19 antibodies among individuals in a community are crucial for herd immunity against the virus. In general, recovered COVID-19 patients have high antibody levels as a result of their natural immune reactions. However, antibody levels in some recovered COVID-19 patients have been seen to drop rapidly over the course of a few weeks, and the underlying mechanism of this phenomenon remains poorly understood.

Since the beginning of the pandemic, research studies have revealed changes in plasma cytokine and metabolite levels in COVID-19 patients. Based on these observations, a research team led by Professor Cai Zongwei, Chair Professor of the Department of Chemistry and Director of the State Key Laboratory of Environmental and Biological Analysis, and Dr Yang Zhu, the first author of this paper and a Research Assistant Professor of the Department of Chemistry at HKBU, investigated how plasma cytokines and metabolites are associated with antibody levels in recovered COVID-19 patients.

Metabolite gly-pro associated with antibody levels

The research team analysed the cytokine and metabolite profiles in the plasma samples of three subject groups. The first group included 17 recovered COVID-19 patients with steady COVID-19 antibody levels; the second group included 30 recovered COVID-19 patients with rapidly fading COVID-19 antibody levels; the third one was a control group comprising 35 individuals who had not been infected with COVID-19.

A series of quantitative computational analyses that involved the use of machine learning techniques were used to compare the levels of different plasma cytokines and metabolites in the three subject groups in relation to their COVID-19 antibody levels. The researchers then compared the two recovered patient groups with the control group, and any cytokines and metabolites with significantly different levels between the two groups and the control group were shortlisted. Among the shortlisted targets, the levels of seven cytokines and 20 metabolites were seen to differ significantly between the two groups of recovered COVID-19 patients.

The researchers then analysed the association between the selected cytokines and metabolites and COVID-19 antibody levels in recovered patients. From the collected data, they concluded that the plasma concentration of the metabolite gly-pro had increased the most in the two recovered patient groups compared with the control group.

Overall, the levels of gly-pro in the recovered patient group with rapidly fading antibody levels were four times higher than the control group, while the levels of gly-pro in the recovered patient group with steady COVID-19 antibody levels were two-and-a-half times higher than the control group. Based on these results, the researchers investigated the relationship between COVID-19 antibody levels in recovered patients and gly-pro, as well as the producing enzyme of gly-pro which is named dipeptidyl peptidase-4 (DPP4).

Inhibiting gly-pro maintains steady antibody levels

The research team set up a four-week mouse model experiment to test the hypothesis that high gly-pro levels are associated with a rapid drop in COVID-19 antibody levels in recovered COVID-19 patients. Four groups of 12 mice were injected with the spike protein of the COVID-19 virus. The groups were then respectively treated with: (1) exogenous gly-pro; (2) an inhibitor that blocks the degradation of endogenous gly-pro; (3) exogenous gly-pro and a DPP4 inhibitor (Sitagliptin, which is also an anti-diabetic drug); and (4) saline.

The serum COVID-19 antibody levels in all groups were similar in the first week of the experiment. The antibody levels of the mice in the first group declined after the second week, suggesting that increased gly-pro levels are associated with a decline in COVID-19 antibody levels. The antibody levels of the mice in the second group, who had relatively steady gly-pro levels, also began to decline in the third week. The slower decline in antibody levels in the second group of mice compared to the first group shows that varying amounts of gly-pro are associated with the amount of time a steady antibody level can be maintained.

Meanwhile, the antibody levels of the mice in the third group remained stable throughout the experiment. This shows that when the activities of DPP4 are inhibited, the negative effects of gly-pro can be neutralised, and a steady level of COVID-19 antibodies can be maintained.

New insights for therapeutic and disease control strategies

Professor Cai said: “Effective shield immunity for a community against the spread of COVID-19 is highly dependent on the maintenance of steady antibody levels in individuals. Our experimental results suggest that DPP4 inhibitors can effectively maintain steady antibody levels in COVID-19-infected mice. As a result, our study offers important insights into how we can develop a similar medical approach to maintain COVID-19 antibody levels in humans, which will contribute to the global fight against the pandemic.”

Dr Yang said: “Further studies based on our research findings are warranted to explore the potential in other areas of therapeutic and disease control, especially in terms of other applications. For example, novel strategies may be developed to enhance the efficiency of vaccination in boosting antibody levels in humans, particularly in diabetic patients, a well-known high-risk population for COVID-19.”