Migrasomes: From Biogenesis, Release, Uptake, Rupture to Homeostasis and Diseases.

Migrasomes are migration-dependent membrane-bound vesicular structures that contain cellular contents and small vesicles. Migrasomes grow on the tips or intersections of the retraction fibers after cells migrate away. The process of releasing migrasomes into the extracellular space is named as "migracytosis". After releasing, they can be taken up by the surrounding cells, or rupture and further release their contents into the extracellular environment. Physiologically, migrasomes provide regional cues for organ morphogenesis during zebrafish gastrulation and discard the damaged mitochondria in response to mild mitochondrial stresses. Pathologically, migrasomes are released from podocyte during early podocyte stress and/or damage, from platelets after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), from microglia/macrophages of the ischemic brain, and from tumor necrosis factor α (TNFα)-activated endothelial cells (ECs); thus, this newly discovered extracellular vesicle is involved in all these pathological processes. Moreover, migrasomes can modulate the proliferation of cancer cell via lateral transferring mRNA and protein. In this review, we will summarize the biogenesis, release, uptake, and rupture of migrasomes and discuss its biological roles in development, redox signalling, innate immunity and COVID-19, cardio-cerebrovascular diseases, renal diseases, and cancer biology, all of these highlight the importance of migrasomes in modulating body homeostasis and diseases.

Noble Gases Therapy in Cardiocerebrovascular Diseases: The Novel Stars?

Cardiocerebrovascular diseases (CCVDs) are the leading cause of death worldwide; therefore, to deeply explore the pathogenesis of CCVDs and to find the cheap and efficient strategies to prevent and treat CCVDs, these are of great clinical and social significance. The discovery of nitric oxide (NO), as one of the endothelium-derived relaxing factors and its successful utilization in clinical practice for CCVDs, provides new ideas for us to develop drugs for CCVDs: "gas medicine" or "medical gases." The endogenous gas molecules such as carbon monoxide (CO), hydrogen sulfide (H2S), sulfur dioxide (SO2), methane (CH4), and hydrogen (H2) have essential biological effects on modulating cardiocerebrovascular homeostasis and CCVDs. Moreover, it has been shown that noble gas atoms such as helium (He), neon (Ne), argon (Ar), krypton (Kr), and xenon (Xe) display strong cytoprotective effects and therefore, act as the exogenous pharmacologic preventive and therapeutic agents for CCVDs. Mechanistically, besides the competitive inhibition of N-methyl-D-aspartate (NMDA) receptor in nervous system by xenon, the key and common mechanisms of noble gases are involved in modulation of cell death and inflammatory or immune signals. Moreover, gases interaction and reduction in oxidative stress are emerging as the novel biological mechanisms of noble gases. Therefore, to investigate the precise actions of noble gases on redox signals, gases interaction, different cell death forms, and the emerging field of gasoimmunology, which focus on the effects of gas atoms/molecules on innate immune signaling or immune cells under both the homeostatic and perturbed conditions, these will help us to uncover the mystery of noble gases in modulating CCVDs.

Scutellaria barbata Inhibits Hepatocellular Carcinoma Tumorigenicity by Inducing Ferroptosis of Hepatocellular Carcinoma Cells.

Ferroptosis is caused by accumulation of iron-dependent lipid peroxidation, which is characterized by reduction in cell volume and increase in mitochondrial membrane density. Studies have shown that ferroptosis contributes to the development and progression of numerous major diseases, including hepatocellular carcinoma (HCC). As a unique biomedical resource, Traditional Chinese Medicine (TCM) has been widely used in the treatment of HCC. In this present study, Scutellaria barbata was used to treat HCC cells in vitro, and the results revealed that S. barbata suppressed HCC cell growth through inducing ferroptosis. Next, the exploration of the molecular mechanism on how S. barbata induced ferroptosis in HCC cells suggested that S. barbata may induce ferroptosis by promoting iron perioxidation and lipid ROS metabolism. Finally, S. barbata also inhibited HCC tumorigenicity in vivo by inducing ferroptosis of HCC cells. These results provided theoretical basis for explaining the mechanism of TCM treatment for HCC and offered therapeutic opportunities for HCC patients.

Helium Protects Against Lipopolysaccharide-Induced Cardiac Dysfunction in Mice via Suppressing Toll-Like Receptor 4-Nuclear Factor κB-Tumor Necrosis Factor-Alpha/ Interleukin-18 Signaling.

The nonanesthetic noble gas helium (He) can protect many organs against ischemia and reperfusion injury, such as liver and heart. However, the role of He on cardiac dysfunction during sepsis is not clear. In this study, we established a lipopolysaccharide (LPS)-induced cardiac dysfunction mouse model to examine the influence of He on the impaired cardiac function, and further investigated the possible innate immune mechanisms that may be involved. LPS induced left ventricular dysfunction and cavity enlargement, as indicated by decreased percent ejection fraction, percent fractional shortening, left ventricular anterior wall thickness in systole, and left ventricular posterior wall thickness in systole, while increased left ventricular end-systolic diameter and left ventricular end-systolic volume. He improved the impaired left ventricular function and cavity enlargement in a dose-dependent manner, and it was beneficial at 1.0 mL/100 g. Mechanistically, He inhibited toll-like receptor 4 (TLR4) expression, reduced the phosphorylation of nuclear factor κB (NF-κB), and subsequently alleviated tumor necrosis factor-alpha (TNF-α) and interleukin-18 (IL-18) expression in heart. Therefore, He protects against LPS-induced cardiac dysfunction in mice partially via inhibiting myocardial TLR4-NF-κB-TNF-α/IL-18 signaling.

Si-Wu-Tang Alleviates Nonalcoholic Fatty Liver Disease via Blocking TLR4-JNK and Caspase-8-GSDMD Signaling Pathways.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has high global prevalence; however, the treatments of NAFLD are limited due to lack of approved drugs. METHODS: Mice were randomly assigned into three groups: Control group, NAFLD group, NAFLD plus Si-Wu-Tang group. A NAFLD mice model was established by feeding with a methionine- and choline-deficient (MCD) diet for four weeks. Si-Wu-Tang was given orally by gastric gavage at the beginning of 3rd week, and it lasted for two weeks. The treatment effects of Si-Wu-Tang were confirmed by examining the change of body weight, serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels, Oil Red O staining, and hematoxylin and eosin (H&E) staining of the liver samples and accompanied by steatosis grade scores. The expression and activation of the possible signaling proteins involved in the pathogenesis of NAFLD were determined by western blotting. RESULTS: Mice fed with four weeks of MCD diet displayed elevated serum levels of ALT and AST, while there was decreased body weight. The hepatic Oil Red O staining and H&E staining showed severe liver steatosis with high steatosis grade scores. All these can be improved by treating with Si-Wu-Tang for two weeks. Mechanistically, the increased hepatic TLR4 expression and its downstream JNK phosphorylation induced by MCD diet were suppressed by Si-Wu-Tang. Moreover, the upregulations of Caspase-8, gasdermin D (GSDMD), and cleaved-GSDMD in liver mediated by MCD diet were all inhibited by Si-Wu-Tang. CONCLUSIONS: Treatment with Si-Wu-Tang improves MCD diet-induced NAFLD in part via blocking TLR4-JNK and Caspase-8-GSDMD signaling pathways, suggesting that Si-Wu-Tang has potential for clinical application in treating NAFLD.

Migrasome and Tetraspanins in Vascular Homeostasis: Concept, Present, and Future.

Cell migration plays a critical role in vascular homeostasis. Under noxious stimuli, endothelial cells (ECs) migration always contributes to vascular repair, while enhanced migration of vascular smooth muscle cells (VSMCs) will lead to pathological vascular remodeling. Moreover, vascular activities are involved in communication between ECs and VSMCs, between ECs and immune cells, et al. Recently, Ma et al. (2015) discovered a novel migration-dependent organelle "migrasome," which mediated release of cytoplasmic contents, and this process was defined as "migracytosis." The formation of migrasome is precisely regulated by tetraspanins (TSPANs), cholesterol and integrins. Migrasomes can be taken up by neighboring cells, and migrasomes are distributed in many kinds of cells and tissues, such as in blood vessel, human serum, and in ischemic brain of human and mouse. In addition, the migrasome elements TSPANs are wildly expressed in cardiovascular system. Therefore, TSPANs, migrasomes and migracytosis might play essential roles in regulating vascular homeostasis. In this review, we will discuss the discoveries of migration-dependent migrasome and migracytosis, migrasome formation, the basic differences between migrasomes and exosomes, the distributions and functions of migrasome, the functions of migrasome elements TSPANs in vascular biology, and discuss the possible roles of migrasomes and migracytosis in vascular homeostasis.

Risk of Developing Hepatocellular Carcinoma following Depressive Disorder Based on the Expression Level of Oatp2a1 and Oatp2b1.

BACKGROUND: Accumulating evidence from prospective epidemiological studies has showed that depression disorder (DD) is a risk factor for cancer. The aim of this study is to explore the association of DD and the overall occurrence risk of hepatocellular carcinoma (HCC) and the mechanism. METHODS: In this study, 60 mice were randomly divided into four groups: Control group, DD group, HCC group, HCC-DD group. Mice received a chronic dose of reserpine to establish depression model, followed by Diethylnitrosamine and Carbon tetrachloride administration to establish HCC models. Behavioral depression was assessed by sucrose preference test (SPT) and the expression of Serotonin 1A (5-HT1A) receptor in the hippocampal. The expression of Oatp2a1 and Oatp2b1 in the digestive system tissues was detected by PCR and western blotting. RESULTS: Reserpine-administrated mice had a reducing sucrose preference at Day 14 compared with blank mice (P<0.05). The expression of 5-HT1A receptor in the hippocampal was decreased in DD mice compared with blank mice. The survival analysis indicated that the HCC mice with DD have poorer survival rate compared with the HCC mice. Compared with HCC mice, the expression of Oatp2a1 and Oatp2b1 was lower in liver and stomach tissue and higher in hepatic carcinoma and colon tissue of HCC-DD mice (P<0.05), and the expression of Oatp2a1 was higher in the spleen tissue of HCC-DD mice while the expression of Oatp2b1 was lower (P<0.05). However, no difference was found in the expression of Oatp2a1 and Oatp2b1 in the small intestine tissue between HCC group and HCC-DD group. CONCLUSIONS: DD was the adverse factors for the overall occurrence risk of HCC. Mechanistically, be the downregulation of Oatp2a1 and Oatp2b1 in liver tissue induced by DD might be involved.

Traditional Chinese Medicine Syndrome Patterns and Their Association with Hepatitis B Surface Antigen Levels during the Natural History of Chronic Hepatitis B Virus Infection.

The aim of this study is to investigate traditional Chinese medicine syndrome (TCMS) patterns and their association with hepatitis B surface antigen (HBsAg) levels during the natural history of chronic hepatitis B virus infection (CHB). Patients were categorized according to the phase of CHB, as follows: immune tolerance (ITP); immune clearance (ICP); low or nonreplication (LRP); reactivation (RAP); hepatic cirrhosis (HC); and primary liver cancer (PLC). TCMS patterns were classified among the following types: spleen-kidney deficiency (SKD); liver-qi depression (LQD); damp-heat in liver-gallbladder (LGDH); liver-kidney deficiency (LKD); and blood stasis blocking collateral (BSBC). HBsAg levels and other serological indicators were quantified for all patients and their association with TCMS was statistically analyzed and determined. Two hundred and eighty-nine patients with CHB were included. During the natural history of CHB, TCMS patterns were statistically different among the different phases (P < 0.001). The most frequently occurring syndromes among the six progressive phases were SKD, LGDH, LKD, LGDH, BSBC, and LGDH, respectively. The predominant patterns in the inactive stage (ITP + LRP), active stage (ICP + RAP), and late or advanced stage (HC + PLC) were SKD (31%), LGDH (51.8%) and BSBC (34.4%), respectively. Median HBsAg levels were also statistically different among the five patterns of TCMS (P < 0.001). The highest HBsAg levels were observed in SKD (4.48 log10 IU/mL). Medium levels were in LQD (3.91 log10 IU/mL) and LGDH (3.90 log10 IU/mL). The lowest HBsAg levels were in LKD (3.60 log10 IU/mL) and the second lowest levels in BSBC (3.81 log10 IU/mL). In addition, HBsAg levels in LKD and BSBC were significantly lower than those in SKD, LQD, and LGDH (P < 0.05 or 0.001). TCMS was altered during the natural history of CHB and correlated with HBsAg titers. This study could provide further insight into the therapy of CHB.

Prognostic value of hsa-mir-299 and hsa-mir-7706 in hepatocellular carcinoma.

This study aimed to investigate the expression of microRNA (miRNA) 299 and miRNA-7706 in patients with hepatocellular carcinoma (HCC), and to explore their effects on proliferation of SK-HEP-1 HCC cells. Expression of miRNA-299 and miRNA-7706 in tumor tissue (HCC group) and adjacent healthy tissue (>30 mm away from the tumor tissue) of 179 patients with HCC was determined by real-time polymerase chain reaction (qRT-PCR). miR-299 mimics and miR-7706 mimics were transfected into SK-HEP-1 HCC cells by RNA transfection. The proliferation and invasion of SK-HEP-1 cells were detected by CCK-8 kit and Transwell kit, respectively. Compared with adjacent tissues, expression levels of miRNA-299 and miRNA-7706 in HCC group were significantly downregulated. Analyses on the correlation between the expression of miRNA-299 and miRNA-7706 and clinical factors showed that expression levels of miRNA-299 and miRNA-7706 were significantly correlated with pathological stages and lymph node metastasis. ROC curve analysis showed that the areas under the curve were 0.837 and 0.845 for miRNA-299 and miRNA-7706 in the prediction of HCC, respectively. Survival analysis showed that the 5-year overall survival rate of patients with high expression levels of miRNA-299 and miRNA-7706 was significantly different from that of patients with low expression levels (P=0.016). Compared with cells transfected with scramble mimics, proliferation and invasion abilities of SK-HEP-1 cells transfected with miR-299 mimics and miRNA-7706 were significantly weakened. Results suggested that downregulation of miRNA-299 and miRNA-7706 can inhibit the proliferation of HCC cells and can be used as a new target for the treatment of HCC.

Hepatocellular carcinoma and hepatitis B surface protein.

The tumorigenesis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) has been widely studied. HBV envelope proteins are important for the structure and life cycle of HBV, and these proteins are useful for judging the natural disease course and guiding treatment. Truncated and mutated preS/S are produced by integrated viral sequences that are defective for replication. The preS/S mutants are considered "precursor lesions" of HCC. Different preS/S mutants induce various mechanisms of tumorigenesis, such as transactivation of transcription factors and an immune inflammatory response, thereby contributing to HCC. The preS2 mutants and type II "Ground Glass" hepatocytes represent novel biomarkers of HBV-associated HCC. The preS mutants may induce the unfolded protein response and endoplasmic reticulum stress-dependent and stress-independent pathways. Treatments to inhibit hepatitis B surface antigen (HBsAg) and damage secondary to HBsAg or the preS/S mutants include antivirals and antioxidants, such as silymarin, resveratrol, and glycyrrhizin acid. Methods for the prevention and treatment of HCC should be comprehensive.

Correlation between Traditional Chinese Medicine symptom patterns and serum concentration of zinc, iron, copper and magnesium in patients with hepatitis B and associated liver cirrhosis.

OBJECTIVE: To investigate the correlation between the patterns of Traditional Chinese Medicine (TCM) syndromes and the serum concentration of zinc, iron, copper and magnesium of patients with chronic hepatitis B (CHB) and hepatitis B virus (HBV)-induced liver cirrhosis. METHODS: A total of 86 patients were included in the study between March 1, 2009 and January 1, 2010. All were diagnosed with CHB or HBV-induced liver cirrhosis according to the diagnosis standard of the Chinese Medical Association. Fasting serum concentrations of zinc, iron, copper and magnesium were measured. Patients were classified into different patterns of TCM symptoms according to TCM theory and clinical experience. RESULTS: In the HBV-induced liver cirrhosis group, the mean zinc concentration in patients with the TCM pattern of stagnation of fluid-Dampness was lower than that in patients with obstruction of collaterals by Blood stasis (P < 0.034). In the CHB group, the mean magnesium concentration in patients with toxic Heat flourishing was significantly lower than that in those with Damp-Heat in the Liver and Gallbladder, and those with Liver depression and Spleen deficiency (P < 0.021). The concentrations of iron and copper showed little difference among the different TCM symptom patterns. CONCLUSION: The serum zinc and magnesium concentrations correlated with certain TCM patterns of symptoms in patients with HBV-induced liver cirrhosis and CHB. It may be helpful to interpret the pathogenic change in the TCM symptom patterns in liver cirrhosis and CHB, and also to conduct clinical treatment of the diseases based on identified TCM patterns.

Changes in serum alanine aminotransferase levels in telbivudine versus lamivudine treatment for chronic hepatitis B: a meta-analysis.

OBJECTIVE: A meta-analysis to compare the efficacy and safety of telbivudine (TBV) and lamivudine (LAM) in patients with chronic hepatitis B (CHB), assessed via changes in serum alanine aminotransferase (ALT) levels. METHOD: The electronic literature databases PubMed®, Embase®, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine and China National Knowledge Infrastructure were searched for relevant studies. The effect of TBV and LAM treatment on serum ALT was assessed using standard mean differences (SMDs) and 95% confidence intervals (CI). RESULTS: The meta-analysis included six studies (TBV n = 202; LAM, n = 208). Post-treatment ALT levels were significantly lower than pretreatment values for both TBV and LAM (TBV: SMD = 3.00, 95%CI 1.91, 4.09; LAM: SMD = 2.33, 95%CI 1.58, 3.07). Post-treatment ALT was significantly lower after treatment with TBV than LAM (SMD = 0.58, 95%CI 0.21, 0.94). CONCLUSION: Both LAM and TBV are effective in normalizing ALT levels in patients with CHB, but TBV may be a better choice due to its lower rates of drug resistance.

Chinese medicine syndrome distribution of chronic hepatitis B virus carriers in immunotolerant phase.

OBJECTIVE: To explore Chinese medicine (CM) syndrome distribution of chronic hepatitis B virus (HBV) carriers in immunotolerant phase (ITP). METHODS: One hundred and eighty-five chronic HBV carriers in ITP, seen in the Third Affiliated Hospital of Sun Yat-sen University from May 2009 to December 2010, were admitted in an observational study under the guidance of CM. Patients' CM symptoms and signs, demographics, liver biochemistries, and qualitative HBV DNA were recorded in the questionnaires. CM syndromes were then differentiated to 15 detailed types and analyzed by generalization. Lastly, the location, pathogenic factors and nature of the disease were also assessed. RESULTS: When CM syndrome patterns were differentiated to 15 types, there were 27 (15%) no syndrome cases, 94 (50%) single syndrome cases and 64 (35%) compound syndromes cases. The main detailed syndromes included Liver (Gan)-qi depression (LQD), Kidney (Shen)-qi deficiency (KQD), Spleen (Pi)-qi deficiency (SQD) and Kidney-yang deficiency (KYAD). After CM syndromes generalized to five types, their frequency was Spleen-Kidney deficiency (SKD)>LQD>inner dampness-heat retention (IDHR)>Liver-Kidney deficiency (LKD)>blood stasis blocking collateral (BSBC). SKD and LQD occupied 64%. The disease location included Liver, Gallbladder (Dan), Spleen, Stomach (Wei) and Kidney. The pathogenic factors were mainly qi stagnation, qi deficiency, yang deficiency, concurrently dampness-heat and blood stasis. The deficiency syndrome was more than excess syndrome in its nature. CONCLUSIONS: Most of chronic HBV carriers in ITP have their CM syndrome, and the most common types are SKAD, LQD. This study suggests that the natural history may be improved through breaking the state of immune tolerance or shorten the time of ITP by strengthening Spleen-Kidney and reliving Liver qi.

[Relationship between traditional Chinese medicine syndrome types and serum HBV DNA level in chronic HBV carriers positive for HBeAg].

OBJECTIVE: To explore the relationship between the syndrome types in traditional Chinese medicine (TCM) and serum HBV DNA load in chronic HBV carriers positive for HBeAg. METHODS: According to the TCM syndrome types, 185 chronic HBV carriers with HBeAg positivity were classified into single syndrome group (liver Qi depression, kidney Qi deficiency, spleen Qi deficiency, and kidney Yang deficiency), compound syndrome group, and unidentifiable syndrome group; based on the nature of the condition in TCM terms, the patients were classified into excess syndrome group, deficiency syndrome group and comorbidity syndrome group. The serum HBV DNA levels in these cases were analyzed in relation to the TCM syndrome types and disease nature. RESULTS: HBV DNA levels showed no significant difference among the patients with single syndrome, compound syndromes and unidentifiable syndrome (F=0.910, P=0.404), nor among the patients with the 5 different single TCM syndromes (χ²=4.672, P=0.323) or those with different disease nature (F=0.631, P=0.596). CONCLUSION: Serum HBV DNA level can not be considered as the evidence for syndrome differentiation in chronic HBV carriers with positive HBeAg.