Effects of hepatitis B virus infection and strategies for preventing mother-to-child transmission on maternal and fetal T-cell immunity.

One of the most common routes of chronic hepatitis B virus (HBV) infection is mother-to-child transmission (MTCT). Approximately 6.4 million children under the age of five have chronic HBV infections worldwide. HBV DNA high level, HBeAg positivity, placental barrier failure, and immaturity of the fetal immune are the possible causes of chronic HBV infection. The passive-active immune program for children, which consists of the hepatitis B vaccine and hepatitis B immunoglobulin, and antiviral therapy for pregnant women who have a high HBV DNA load (greater than 2 × 105 IU/ml), are currently two of the most important ways to prevent the transmission of HBV from mother to child. Unfortunately, some infants still have chronic HBV infections. Some studies have also found that some supplementation during pregnancy can increase cytokine levels and then affect the level of HBsAb in infants. For example, IL-4 can mediate the beneficial effect on infants' HBsAb levels when maternal folic acid supplementation. In addition, new research has indicated that HBV infection in the mother may also be linked to unfavorable outcomes such as gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, and premature rupture of membranes. The changes in the immune environment during pregnancy and the hepatotropic nature of HBV may be the main reasons for the adverse maternal outcomes. It is interesting to note that after delivery, the women who had a chronic HBV infection may spontaneously achieve HBeAg seroconversion and HBsAg seroclearance. The maternal and fetal T-cell immunity in HBV infection is important because adaptive immune responses, especially virus-specific CD8 T-cell responses, are largely responsible for viral clearance and disease pathogenesis during HBV infection. Meanwhile, HBV humoral and T-cell responses are important for the durability of protection after fetal vaccination. This article reviews the literature on immunological characteristics of chronic HBV-infected patients during pregnancy and postpartum, blocking mother-to-child transmissions and related immune mechanisms, hoping to provide new insights for the prevention of HBV MTCT and antiviral intervention during pregnancy and postpartum.

Microstructural Analysis of Cancellous Bone in Fluorosis Rats.

Skeletal fluorosis likely alters bone structural properties on the cortical and cancellous tissue levels in view that fluorine ion replaces bone mineral composition. Our previous study showed high bone turnover occurred in cortical bone of skeletal fluorosis. Therefore, this study further analyzed the microstructure of cancellous bone in fluorosis rats. Rats were randomly assigned into three groups: the control, low-dose fluoride group (10 mgF-/kg·day), and high-dose fluoride group (20 mgF-/kg·day). Rats were orally administered with fluoride for 1, 2, and 3 months of periods. The trabecular bone parameters of tibia were detected with micro CT and analyzed with software. The activities of glutathione peroxidase (GPX), superoxide dismutase (SOD), and the content of malondialdehyde (MDA) in serum were measured. Results showed that severity of dental fluorosis rose with the increase of dose and prolongation of fluoride exposure. Meantime, the poorer connectivity and less trabecular bone network were observed in cancellous bone of rats treated with fluoride. Data analysis indicated that fluoride treatment significantly decreased bone volume and connectivity degree, but amplified trabecular space in 1 and 2 months of periods. Intriguingly, trabecular thickness significantly decreased in 1-month high-dose fluoride group, but returned to the control in 3 months of period. Fluoride treatment mainly inhibited the GPX activity and increased the MDA level to activate oxidative stress. This study confirmed that excessive fluoride impaired cancellous bone and caused redox imbalance.

The inhibitory effect and mechanism of Yi-qi-hua-yu-jie-du decoction on the drug resistance of gastric cancer stem cells based on ABC transporters.

BACKGROUND: The drug resistance of tumor stem cells is an obstacle in gastric cancer (GC) treatment and the high expression of ABC transporters is a classic reason for drug resistance. This study aimed to construct a reliable GC drug-resistant stem cell model and explore the inhibitory effect and mechanism of Yi-qi-hua-yu-jie-du medicated serum (YQHY) on the drug resistance of GC stem cells based on ABC transporters. METHODS: The tumor stemness biomarker CD44 was primary identification from WGCNA. The magnetic-activated cell sorting (MACS) method was used to separate CD44( +)BGC823/5-Fu (BGC823/5-Fu-CSCs) cells and the stemness characteristics were verified from multiple dimensions. Then, the drug resistance index and expression of ABC transporter genes MDR1 and MRP1 were detected in CD44(-)/CD44(+) cells. The inhibition and apoptosis rates of the cells administrated with YQHY or/and 5-Fu were calculated to confirm that YQHY can suppress the drug resistance of BGC823/5-Fu-CSCs. Afterwards, the effects of YQHY on the expression of MDR1 and MRP1 and the activation of the PI3K/Akt/Nrf2 pathway were observed. Finally, under the administration of IGF-1 (the activator of PI3K/Akt pathway) and Nrf2 siRNA, the mechanism of YQHY on reversing the drug resistance of BGC823/5-Fu-CSCs through inhibiting the expression of MDR1 and MRP1 via PI3K/Akt/Nrf2 was verified. RESULTS: CD44 was a reliable GC stemness biomarker and can be applied to construct the drug-resistant GC stem cell model CD44(+)BGC823/5-Fu. The growth rate, cell proliferation index, soft agar colony formation, expression of stemness specific genes and tumorigenesis ability of CD44(+)BGC823/5-Fu cells were significantly higher than those of CD44(-)BGC823/5-Fu cells. BGC823/5-Fu-CSCs exhibited strong drug resistance to 5-Fu and high expression of ABC transporter genes MDR1 and MRP1 compared to CD44(-) cells. YQHY increased the inhibition and apoptosis rates to efficiently inhibit the drug resistance of BGC823/5-Fu-CSCs. Meanwhile, it suppressed the expression of MDR1 and MRP1 and restrained the activation of PI3K/Akt/Nrf2 signaling pathway. Finally, it was found that IGF-1 partially restored the activation of PI3K/Akt/Nrf2 pathway, alleviated the inhibition of MDR1 and MRP1, blocked the proliferation-inhibitory and apoptosis-promotion effects. YQHY and si-Nrf2 synergistically suppressed the MDR1/MRP1 expression and the drug resistance of BGC823/5-Fu-CSCs. CONCLUSIONS: CD44 was a reliable GC stemness biomarker, and the high expression of ABC transporter genes MDR1 and MRP1 was an important feature of drug-resistant stem cells. YQHY inhibited the MDR1 and MRP1 expression via PI3K/Akt/Nrf2 pathway, thus reversing the drug resistance of BGC823/5-Fu-CSCs.

Study on the mechanism of active components of Liupao tea on 3CLpro based on HPLC-DAD fingerprint and molecular docking technique.

Liupao tea, a drink homologous to medicine and food. It can treat dysentery, relieve heat, remove dampness, and regulate the intestines and stomach. The objective of this study is to explore the material basis and mechanism of Liupao tea intervention in COVID-19 and to provide a new prevention and treatment programme for COVID-19. We used high performance liquid chromatography to analyze the extract of Liupao tea and establish its fingerprint. The main index components of the fingerprint were determined using SARS-COV-2 3-chymotrypsin-like protease (3CLpro ), and an in vitro drug screening model based on fluorescence resonance energy transfer was used to evaluate its inhibitory activity in vitro. The fingerprint results showed that the alcohol extract of Liupao tea contained gallic acid, epigallocatechin gallate (EGCG), caffeine, epicatechin gallate, rutin, and ellagic acid. The molecular docking binding energies of the six index components of SARS-CoV-2 3Clpro were all less than -5.0 kJ/mol and showed strong binding affinity. The results of in vitro activity showed that the IC50 of EGCG was 8.84 µmol/L, which could inhibit SARS-CoV-2 3Clpro to a certain extent. This study unleashed that EGCG has a certain inhibitory effect on SARS-CoV-2 3CLpro , and Liupao tea has a certain significance as a tea drink for the prevention of COVID-19. PRACTICAL APPLICATIONS: The objective of this study was to explore the material basis and mechanism of Liupao tea intervention in COVID-19 and to provide a new prevention and treatment programme for COVID-19. The molecular docking binding energies of the six index components of Liupao tea with SARS-CoV-2 3CLpro were all less than -5.0 kJ/mol, among them, the enzyme activity experiment shows that EGCG has a certain inhibitory effect on SARS-CoV-2 3CLpro , it can be used as a potential SARS-CoV-2 3CLpro inhibitor. We predicted that the understandings gained in the current research may evidence that Liupao tea has a certain significance as a tea drink for the prevention of COVID-19.

Zhenbao pill attenuates hydrogen peroxide-induced apoptosis by inhibiting autophagy in human umbilical vein endothelial cells.

ETHNOPHARMACOLOGICAL RELEVANCE: The Zhenbao pill (ZBP) is composed of 29 traditional Chinese medicines and has been proven to exhibit a valid therapeutic effect in nervous system diseases, such as stroke and hemiplegia sequelae. AIM OF THE STUDY: Whether ZBP has a protective effect on vascular endothelial cells remains unknown. In this study, we established hydrogen peroxide (H2O2)-induced oxidative injury in human umbilical vein endothelial cells (HUVECs) as an in vitro model to investigate the pharmacological effects of ZBP. MATERIALS AND METHODS: Following the intragastric administration of ZBP (0.25, 0.5, and 1 g/kg for seven days) in rats, drug-containing serum was obtained and cultivated with HUVECs before H2O2 treatment. The viability of HUVECs in the presence of H2O2 was measured by Cell Counting Kit-8 assay, lactate dehydrogenase assay, and flow cytometry. Furthermore, we estimated the effects of ZBP on the production of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Autophagic puncta were detected using a fluorescence microscope. Western blotting and real-time polymerase chain reaction were used to detect the expression levels of several genes associated with apoptosis and autophagy. RESULTS: Drug-containing serum separated from rats at 1 h after intragastric administration of ZBP (0.5 g/kg) significantly offered a protective effect to HUVECs and reduced cell apoptosis rates. Meanwhile, ZBP-containing serum also repressed ROS production induced by H2O2 exposure and maintained MMP. Further investigation revealed that ZBP-containing serum effectively reduced the accumulation of autophagic puncta. ZBP-mediated inhibition on cell autophagy was found to contribute to ameliorating cell apoptosis. Western blotting also confirmed that ZBP maintained AKT and mTOR phosphorylation and antagonized the imbalance of BCL2/BAX, thereby protecting cells from apoptosis. CONCLUSION: Taken together, our data indicate that ZBP inhibits ROS production, mitochondrial damage, cell autophagy, and cell apoptosis. ZBP can offer protection to vascular endothelial cells against oxidative injury through the antagonism of apoptosis and autophagy. Thus, this study enhances the understanding of the therapeutic effects and mechanisms of ZBP in the process of recovery from myocardial and cerebral ischemic stroke.

Study of the active ingredients and mechanism of Sparganii rhizoma in gastric cancer based on HPLC-Q-TOF-MS/MS and network pharmacology.

Sparganii rhizoma (SL) has potential therapeutic effects on gastric cancer (GC), but its main active ingredients and possible anticancer mechanism are still unclear. In this study, we used HPLC-Q-TOF-MS/MS to comprehensively analyse the chemical components of the aqueous extract of SL. On this basis, a network pharmacology method incorporating target prediction, gene function annotation, and molecular docking was performed to analyse the identified compounds, thereby determining the main active ingredients and hub genes of SL in the treatment of GC. Finally, the mRNA and protein expression levels of the hub genes of GC patients were further analysed by the Oncomine, GEPIA, and HPA databases. A total of 41 compounds were identified from the aqueous extract of SL. Through network analysis, we identified seven main active ingredients and ten hub genes: acacetin, sanleng acid, ferulic acid, methyl 3,6-dihydroxy-2-[(2-hydroxyphenyl) ethynyl]benzoate, caffeic acid, adenine nucleoside, azelaic acid and PIK3R1, PIK3CA, SRC, MAPK1, AKT1, HSP90AA1, HRAS, STAT3, FYN, and RHOA. The results indicated that SL might play a role in GC treatment by controlling the PI3K-Akt and other signalling pathways to regulate biological processes such as proliferation, apoptosis, migration, and angiogenesis in tumour cells. In conclusion, this study used HPLC-Q-TOF-MS/MS combined with a network pharmacology approach to provide an essential reference for identifying the chemical components of SL and its mechanism of action in the treatment of GC.

The inhibition of Mpro, the primary protease of COVID-19, by Poria cocos and its active compounds: a network pharmacology and molecular docking study.

Poria cocos is a traditional Chinese medicine (TCM) that can clear dampness, promote diuresis, and strengthen the spleen and stomach. Poria cocos has been detected in many TCM compounds that are used for COVID-19 intervention. However, the active ingredients and mechanisms associated with the effect of Poria cocos on COVID-19 remain unclear. In this paper, the active ingredients of Poria cocos, along with their potential targets related to COVID-19, were screened using TCMSP, GeneCards, and other databases, by means of network pharmacology. We then investigated the active components, potential targets, and interactions, that are associated with COVID-19 intervention. The primary protease of COVID-19, Mpro, is currently a key target in the design of potential inhibitors. Molecular docking techniques and molecular dynamics simulations demonstrated that the active components of Poria cocos could bind stably to the active site of Mpro with high levels of binding activity. Pachymic acid is based on a triterpene structure and was identified as the main component of Poria cocos; its triterpene active component has low binding energy with Mpro. The pachymic acid of Mpro activity was further characterized and the IC50 was determined to be 18.607 µmol L-1. Our results indicate that pachymic acid exhibits a certain inhibitory effect on the Mpro protease.

Multidrug Resistance of Gastric Cancer: The Mechanisms and Chinese Medicine Reversal Agents.

Chemotherapy is the main clinical treatment method of gastric cancer. Multidrug resistance (MDR) has become a common phenomenon with the development of tumors, which alleviates the effect of chemotherapy and makes it difficult to break the bottleneck of survival rate of advanced gastric cancer. Therefore, the exploration of MDR reversal agents for gastric cancer is the focus and also the difficulty of current treatment. Currently, the researches on the mechanisms of drug resistance in gastric cancer have been continuously deepened, which reveal different pathways and targets of MDR, laying a solid foundation for studying reversal agents. As a kind of natural medicine, traditional Chinese medicine (TCM) owns the characteristics of low toxicity, high safety and effectiveness. It can inhibit the occurrence, growth and metastasis of tumors, and reverse MDR via multiple pathways and mechanisms, the pathological function of which has become a research hotspot in recent years. TCM reversers are mainly divided into Chinese medicine monomers, Chinese patent medicines, and Chinese herbal compounds. With certain quantity and advantage, TCM reversers for MDR play an important role in the clinical treatment and show great potential in gastric cancer.

A Series of Novel HDAC Inhibitors with Anthraquinone as a Cap Group.

Although anthraquinone derivatives possess significant antitumor activity, most of them also displayed those side effects like cardiotoxicity, mainly owing to their inhibition of topoisomerase II of DNA repair mechanisms. Our raised design strategy by switching therapeutic target from topoisomerase II to histone deacetylase (HDAC) has been applied to the design of anthraquinone derivatives in current study. Consequently, a series of novel HDAC inhibitors with a tricylic diketone of anthraquinone as a cap group have been synthesized. After screening and evaluation, compounds 4b, 4d, 7b and 7d have displayed the comparable inhibition in enzymatic activity and cell proliferation than that of Vorinostat (SAHA). Notably, compound 4b showed certain selectivity of antiproliferative effects on cancer cell lines over non-cancer cell lines.

Endophytic fungi from the branches of Camellia taliensis (W. W. Smith) Melchior, a widely distributed wild tea plant.

Camellia taliensis (W. W. Smith) Melchior is a wild tea plant endemic from the west and southwest of Yunnan province of China to the north of Myanmar and is used commonly to produce tea by the local people of its growing areas. Its chemical constituents are closely related to those of C. sinensis var. assamica, a widely cultivated tea plant. In this study, the α diversity and phylogeny of endophytic fungi in the branches of C. taliensis were explored for the first time. A total of 160 fungal strains were obtained and grouped into 42 species from 29 genera, which were identified based on rDNA internal transcribed spacer sequence analysis. Diversity analysis showed that the endophytic fungal community of the branches of C. taliensis had high species richness S (42), Margalef index D' (8.0785), Shannon-Wiener index H' (2.8494), Simpson diversity index DS (0.8891), PIE index (0.8947) and evenness Pielou index J (0.7623) but a low dominant index λ (0.1109). By contrast, that in the branches of C. taliensis had abundant species and high species evenness. Diaporthe tectonigena, Acrocalymma sp. and Colletotrichum magnisporum were the dominant endophytic fungi. The phylogenetic tree was established by maximum parsimony analysis, and the 11 orders observed for endophytic fungi belonging to Ascomycota and Basidiomycota were grouped into 4 classes.