[Current status and challenges of clinical research and development of new drugs for liver diseases].

Liver disease is a serious public health problem worldwide, affecting human health. However, there are still many unmet needs for the treatment of liver disease, especially with new therapeutic drugs. At present, there is no treatment method to eradicate the hepatitis B virus, nor are there therapeutic drugs for liver fibrosis, liver failure, and others. Chemotherapy and targeted immunotherapy are still unsatisfactory for liver cancer. This article provides an overview of the current status and challenges that arise in new drug research and development for liver diseases.

[Clinical status and challenges of new drugs for metabolic dysfunction-associated fatty liver disease].

Metabolic dysfunction-associated fatty liver disease (MASLD) is a major public health problem that seriously affects human health. At present, some good progress has been made in the research and development of new drugs for MASLD, but there is still great space for exploration. This paper summarizes and analyzes the reasons in the current clinical status and challenges for the research and development of new drugs for MASLD.

[Challenges and optimization strategies for clinical research and the development of new drugs for liver fibrosis].

Liver fibrosis is a key step in the developmental process of various chronic liver diseases, including cirrhosis. Therefore, the focus and difficulty of liver disease research have always been on how to reverse liver fibrosis. However, due to complex mechanisms, difficulties in endpoint evaluation, a lack of non-invasive diagnostic methods, and other factors, the research and development of new drugs are hindered and lengthy. Currently, some new drugs are being researched and developed, which signifies the prospect is optimistic.

[Functional recompensation during decompensated-stage cirrhosis].

Recent studies suggest that recompensation of liver function appears in decompensated cirrhosis after effective treatment. However, liver function recompensation degree, recompensation evaluation diagnostic criteria, how to predict recompensation from the perspective of liver function, and others still need to be further explored. Therefore, functional recompensation is explored here from the perspective of decompensated-stage cirrhosis.

[Research progress of liver sinusoidal endothelial cells in nonalcoholic fatty liver disease].

Non-alcoholic fatty liver disease (NAFLD) is widespread worldwide and thereby a very serious public health problem. There are currently no effective drug treatment measures. Liver sinusoidal endothelial cells (LSECs) are the most abundant non-parenchymal cells in the liver; however, it is still not clear what role LSECs play in NAFLD. This article reviews the research progress of LSECs in NAFLD in recent years in order to provide some reference for subsequent research.

[Emotional disorder: a neglected symptoms of chronic liver disease].

Patients with chronic liver disease generally have emotional disorders that typically manifest as depression, and seriously affects the quality of life. The mechanism of emotional disorders in patients with chronic liver disease is unclear, and may be related to variety of factors such as disease type, etiological treatment, economic, social support, and an individual psychology. Moreover, emotional disorders in patients with chronic liver disease can be assessed on a variety of scales and managed comprehensively through non-drug and drug therapy. This article reviews the potential pathogenesis, evaluation and treatment methods, in order to improve and provide more help for its effective treatment.

[An overlooked liver cirrhosis complications: portal vein thrombosis, sarcopenia and hepatic osteopathy].

Liver cirrhosis can lead to a variety of complications. Ascites, hepatic encephalopathy, esophageal variceal bleeding, and hepatorenal syndrome have been well recognized. However, there are still some complications that have a high incidence, but are overlooked by clinicians. These complications will also significantly affect the patient's quality of life and long-term prognosis. In this paper, the overlooked complications of liver cirrhosis, such as portal vein thrombosis, cirrhotic sarcopenia, and hepatic osteopathy and so on, are discussed, and the future research direction and work focus are prospected, in order to attract the attention of clinicians and researchers.

[Risk and control management of endoscopic retrograde cholangiopancreatography in patients with liver cirrhosis].

Endoscopic retrograde cholangiopancreatography (ERCP) is the most direct and effective method for the diagnosis and treatment of biliary and pancreatic diseases. Compared with surgery, ERCP has the advantages of minimal trauma, shorter surgery time, fewer complications, and shorter hospital stay. Liver cirrhosis, as the advanced stage of liver disease, has reduced tolerance to surgical stresses, and complications such as hepatic encephalopathy, esophagogastric varices, and coagulation dysfunction may occur during the decompensated stage, which poses a challenge to ERCP, and thus increase the intraoperative risk and postoperative complications. This article reviews and discusses the indications, risk and control management of ERCP in patients with liver cirrhosis.

[Physical activity intervention for non-alcoholic fatty liver disease in children].

Non-alcoholic fatty liver disease is chronic steatosis of the liver in children and adolescents under 18 years of age, which is related to insulin resistance, obesity and dyslipidemia. Non-alcoholic fatty liver is the most common cause of liver disease in children, and lifestyle interventions such as diet or exercise are usually recommended as a treatment. Compared with dietary restriction that may affect growth and development, physical training has become the main form of treatment for children with non-alcoholic fatty liver disease. This article summarizes the aspects of physical training intervention for non-alcoholic fatty liver disease in children.

[The descending pathophysiology model of cholestatic liver disease].

Intrahepatic cholestasis is a pathological condition in which the synthesis, secretion, and excretion of bile are blocked, and thus the bile does not flow normally into the duodenum and bloodstream. According to cytological damage site, it can be divided into hepatocellular cholestasis, biliary duct cell cholestasis and mixed cell cholestasis. The two kinds of pathophysiological models [ascending or upstream (damage begins with cholangiocytes and then extends to the hepatocytes) and descending or downstream (the damage starts from the liver cells and then extends to the bile duct cells)] has distinct features in the process of disease occurrence and development. This article mainly elaborates the "descending" pathophysiological model of cholestatic liver disease (hepatocytic damage progresses to biliary duct cell), and further explores its etiology, pathogenesis and treatment methods.

[Transforming growth factor beta regulates hepatic progenitor cells migration via PI3K/AKT/mTOR/p70S6K pathway].

Objective: To investigate the effect and mechanism of transforming growth factor ß (TGFß) on the migration ability of hepatic progenitor cells in vitro. Methods: Primary hepatic progenitor cells of male wild-type C57BL/6J mice were isolated by two-step perfusion method and stimulated with different concentrations of TGFß .The morphological changes were observed under phase -contrast microscopy. The effects of TGFß on migration ability of hepatic progenitor cells were evaluated by scratch test and transwell method. Expression profiling and signaling phospho antibody array detected the signaling pathways involved in the regulation of TGFß on hepatic progenitor cells. Protein level of PI3K/AKT/mTOR/p70S6K signaling pathway and the localization of each signaling molecules in hepatic progenitor cells were detected. Data comparison between the two groups was performed by independent sample t-test. One-way ANOVA was used for data comparison between multiple groups. Results: TGFß made the liver progenitor cells from oval to long spindle type. Scratch test showed that the scratch healing rates of 24 h control group, and 2 ng/ml and 10 ng/ml TGF-beta groups were 36.48% ± 4.37%, 57.35% ± 4.60%, and 73.14% ± 5.02% (F = 65.87, P < 0.01), respectively. Transwell test showed that the number of migrating cells in 24 h control group, 2 ng/ml and 10 ng/ml TGF-beta groups were 127 ± 16, 230 ± 18, and 385 ±36 (F = 94.99, P < 0.01), respectively. The results of expression profiling showed that TGFß regulates gene expression in hepatic progenitor cells, and differentially expressed genes participate in the PI3K-AKT signaling pathway. Signaling phospho antibody array and western blot showed that TGFß regulated PI3K/AKT/mTOR/p70S6K signaling pathway in hepatic progenitor cells. Concurrently, immunofluorescence assay showed phosphorylation (p) 70s6k, p AKT1 and PI3K and F-actin co-localizations. Conclusion: TGFß can promote hepatic progenitor cell migration through PI3K/AKT/mTOR/p70S6K pathway, and p70S6K, pAKT1 and PI3K signaling molecules are involved in the regulation of morphology and migration of liver progenitor cells.

[Present situation on non-invasive assessment of liver fibrosis/cirrhosis].

Patients with chronic liver disease often have varying degrees of hepatic fibrosis, and further exacerbations can lead to cirrhosis and even hepatocellular carcinoma. Liver biopsy is the gold standard for the diagnosis of liver fibrosis/cirrhosis, but there are still many limitations. In recent years, non-invasive assessments for liver fibrosis/cirrhosis have gained rapid development. Of these techniques, two different approaches have been validated in clinical practice: imaging methods based on the measurement of liver stiffness, and biological methods based on the serum biomarkers. The two different approaches can complement each other. Current non-invasive assessments for liver fibrosis/cirrhosis tend to be reliable for the detection of advanced fibrosis and cirrhosis, but often lack to distinguish the different early stage of liver fibrosis. Further improving the accuracy of non-invasive assessments might play an important role for clinical management of liver diseases.

[Research advances in epithelial - mesenchymal transition in hepatocellular carcinoma].

Epithelial-mesenchymal transition (EMT) is a process by which epithelial cells lose their own features and become mesenchymal cells, and more and more studies have shown that EMT plays an important role in the invasion and metastasis of hepatocellular carcinoma (HCC). This article reviews the signaling pathways involved in the progression of HCC and molecules involved in the regulation of EMT, in order to provide a new direction for the treatment of HCC.

[Qualitative pathological assessment of liver fibrosis regression after antiviral therapy in patients with chronic hepatitis B].

Objective: To investigate the methods for qualitative pathological assessment of dynamic changes in liver fibrosis/cirrhosis after antiviral therapy in patients with chronic hepatitis B (CHB), since antiviral therapy can partially reverse liver fibrosis and cirrhosis caused by hepatitis B and semi-quantitative, rather than qualitative, pathological assessment is often used for the research on liver fibrosis regression. Methods: Previously untreated CHB patients with liver fibrosis and cirrhosis were enrolled, and liver biopsy was performed before treatment and at 78 weeks after the antiviral therapy based on entecavir. The follow-up assessment was performed once every half a year. Based on the proportion of different types of fibrous septum, we put forward the new qualitative criteria called P-I-R classification (predominantly progressive, predominantly regressive, and indeterminate) for evaluating dynamic changes in liver fibrosis. This classification or Ishak fibrosis stage was used to evaluate the change in liver fibrosis after treatment and Ishak liver inflammation score was used to evaluate the change in liver inflammation after treatment. Results: A total of 112 CHB patients who underwent liver biopsy before and after treatment were enrolled, and among these patients, 71 with an Ishak stage of ≥3 and qualified results of live biopsy were included in the final analysis. Based on the P-I-R classification, 58% (41/71) were classified as predominantly progressive, 29% (21/71) were classified as indeterminate, and 13% (9/71) were classified as predominantly regressive; there were no significant differences between the three groups in alanine aminotransferase, aspartate aminotransferase, albumin, HBeAg positive rate, HBV DNA, and liver stiffness (P < 0.05). After treatment, the proportion of predominantly progressive, indeterminate, or predominantly regressive patients changed to 11% (8/71), 11% (8/71), and 78% (55/71), respectively. Among the 35 patients who had no change in Ishak stage after treatment, 72% (25/35) were classified as predominantly regressive and had certain reductions in the Laennec score, percentage of collagen area, and liver stiffness. Conclusion: This new P-I-R classification can be used to assess the dynamic changes in liver fibrosis after antiviral therapy in CHB patients.

[Progress in diagnosis and therapy of extrahepatic manifestations of cholestatic liver diseases].

Extra-hepatic complications of cholestasis mainly include pruritus, fatigue and metabolic bone diseases, and their molecular mechanisms have not yet been fully identified so far. Though therapeutic regimens targeted at the pathogenesis alleviate the symptoms temporarily, the therapeutic effects are limited, and therefore expounding the pathogenesis will help find more appropriate therapeutic approaches. Pruritus may be caused by nerve conduction block resulting from accumulation of some substances in the accumulated bile, existing recommended methods like drug therapy with cholestyramine and blood purification can markedly alleviate cholestasis-induced pruritus. Fatigue may be a consequence of the central nervous system disorders, and there is currently no specific therapy. Metabolic bone diseases (MBD), also known as hepatic osteodystrophy, are often manifested by osteopenia and osteoporosis, and correcting bad factors responsible for bone loss will help relieve MBD. Bisphosphonate is recommended for treatment of cholestasis-induced osteoporosis. In the event that a patient experiences intolerable pruritus and frequent fractures resulting from osteoporosis, assessment for liver transplantation should be conducted.

[Cholesterol metabolism and non-alcoholic steatohepatitis].

The disease spectrum of non-alcoholic fatty liver disease (NAFLD) includes non-alcoholic simple fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), as well as liver cirrhosis and hepatocellular carcinoma, with the most serious type being NASH. The morbidity of NAFLD is seeing an increase year by year in the world, and it is a common cause of chronic hepatic disease and lacks effective treatment. The pathogenesis of NASH is still unknown, and the "two-hit" hypothesis was used to explain the mechanism of NASH. Recent research has found that cholesterol metabolism is closely related to the pathogenesis and severity of NASH. The validity of the "two-hit" hypothesis has been recently challenged, which gives rise to "multi-parallel hit" hypothesis. Cholesterol affects membrane fluidity and membrane protein function through genetic factors, and it can also induce unfolded protein response, and generate toxic oxysterol. Free cholesterol can activate hepatic Kupffer and stellate cells to produce inflammatory cytokines and collagen. The formation of cholesterol crystallization and crown-like structures can damage liver cells and activate Kupffer cells. The above processes can all aggravate liver damage, thus accelerating the development and making the clinical manifestations of NASH even worse. In the present review we summarize the association between cholesterol metabolism and pathogenesis of NASH.

Myofibroblastic transformation of rat hepatic stellate cells: the role of Notch signaling and epithelial-mesenchymal transition regulation.

OBJECTIVE: The development of liver fibrosis has been shown to be associated with the transition of quiescent hepatic stellate cells (HSCs) into myofibroblastic HSCs, and the Notch signaling system has been shown to be activated in this process. The Notch signaling pathway is also known to regulate epithelial-mesenchymal transition (EMT). MATERIALS AND METHODS: In the current study, quiescent HSCs were examined for expression of EMT markers, and experiments were performed to determine whether these markers change as quiescent HSCs transition into myofibroblastic HSCs and whether the process is modulated by Notch signaling. To promote myofibroblastic transition under experimental conditions, enzymatic perfusion and density gradient centrifugation were used to isolate rat HSCs, which were then cultured. A γ-secretase inhibitor was used to inhibit Notch signaling pathway activity in primary rat HSCs. RESULTS: Upregulated expression of myofibroblastic markers was observed, but expression of quiescent HSC markers and epithelial markers was downregulated during the transition of HSC in vitro. Data indicate that expression of the classical EMT marker; i.e., E-cadherin, was decreased and that of N-cadherin and snail 1 increased. Notch 2 and Notch 3 receptors and Hey2 and HeyL target genes expression increased significantly as quiescent HSCs transitioned into myofibroblastic HSCs. When Notch signaling was blocked, however, the myofibroblastic transition of HSCs reverted, and epithelial marker expression was restored. CONCLUSIONS: Thus, targeting Notch signaling may provide new insights into the mechanism of HSC transition and may offer a possible therapeutic target for the treatment of hepatic injury.

Rapamycin inhibits the proliferation of SW1990 pancreatic cancer cell.

OBJECTIVE: To study the effect of rapamycin on pancreatic cancer cell proliferation, we designed a serial of experiments in human pancreatic cancer cell line SW1990. MATERIALS AND METHODS: SW1990 cells were treated with different concentrations of rapamycin. Cell proliferation was measured by CCK-8 assay and cell colony formation. Cell cycle and apoptosis was analyzed by flow cytometry. The existence of mTOR signaling pathway was demonstrated by immunocytochemistry. Western-blot and real time-PCR were used to test whether mTOR-signaling pathway was inhibited with rapamycin treatment. RESULTS: Our results showed that rapamycin inhibited the cell colony formation and proliferation (p < 0.05). Rapamycin induced G1 cell cycle arrest (p < 0.05) but not cell apoptosis (p > 0.05). p-mTOR, p-p70S6K and p-4E-BP1 were expressed in the cytoplasm of SW1990 cells and those proteins were significantly reduced with rapamycin (p < 0.05). CONCLUSIONS: Rapamycin inhibits SW1990 pancreatic cancer cell proliferation through inhibiting the activation of mTOR pathway.

[The infective state of cytomegalovirus in the infective disease of respiratory tract].

By means of molecular biology and serology, we detect the infective state of cytomegalovirus in 58 patients with infective disease of respiratory tract. The result shows that the infective state of cytomegalovirus exists in the RTID, but there is no virusemia in patients. The immune response of past-infection of cytomegalovirus in the patients of RTID is rather remarkable.