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Background: Intrahepatic cholangiocellular carcinoma (ICC) is one of the most common invasive malignancies. Currently, ICC is treated with radical surgical resection. However, the majority of patients are diagnosed at an advanced stage, making surgery ineligible for them. Case presentation: We present a case of advanced ICC, which could not undergo radical surgery due to tumor invasion of liver blood vessels. The gemcitabine and oxaliplatin (GEMOX) regimen combined with Tislelizumab immunotherapy and Lenvatinib targeted therapy for 8 cycles resulted in significant tumor shrinkage significantly and the vascular invasion disappeared. CA19-9 levels were reduced to normal levels. Partial remission and successful tumor transformation were achieved. The patient underwent a successful radical surgical resection, including cholecystectomy, resection of liver segments IV, V, and VIII, as well as a regional lymphatic dissection procedure, resulting in complete pathological remission. Conclusion: Tumor-free surgical margins (R0) resection of patients with advanced ICC after combination of immune, targeted and chemotherapy is rare, and there are almost no cases of complete postoperative remission. The GEMOX regimen in combination with Tislelizumab and Lenvatinib has a good antitumor efficacy and safety profile, and may be a feasible and safe translational treatment option for advanced ICC.
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Aiming to understand the responses of soil seed bank to different water levels, we investigated vegetation and soil seed bank along a water level gradient (frequently flooded area, unflooded area) on the floodplain wetland of Juzhang River. We used the structural equation model to explore the direct and indirect effects of water level on soil seed bank, and used non-metric multidimensional scaling (NMDS) to assess the role of soil seed bank for vegetation regeneration. The results showed that the density of transient and persistent seed banks at unflooded area was 36.9% and 7.8% higher than that of frequently flooded area, respectively. Shannon index and Pielou index of seed bank and vegetation were significantly affected by water level and sampling location. Water level significantly affected the similarity between seed bank and aboveground vegetation, and the similarity of persistent seed bank with aboveground vegetation was significantly higher than that with transient seed bank. Structural equation model showed that water level had a direct effect on seed bank density, and indirect effects on density and richness of seed bank via affecting soil pH and NH4+-N content. NMDS results showed that there was no significant difference in the composition of the persistent seed bank and vegetation community in autumn under different water levels, but water level significantly changed the community composition of transient seed bank. Transient seed bank was affected by the vegetation and soil property, while persistent seed bank was determined by aboveground vegetation and water level. Although soil seed bank had low regeneration potential for the vegetation communities in floodplain wetlands, soil seed bank could not be neglected during the restoration of propagule diversity after disturbance in wetlands. Persistent seed bank would be an importance source of diversity of propagules for floodplain wetlands restoration following disturbance.
Subject(s)
Rivers , Soil , Wetlands , China , Soil/chemistry , Floods , Conservation of Natural Resources , Seeds/growth & development , Ecosystem , Water Movements , Seed BankABSTRACT
The objective of this review is to elaborate on the status, hotspots, and trends of researches on acupuncture for stroke over the past 26 years. Publications about acupuncture for stroke were downloaded from the Web of Science Core Collection, and these papers were published up to December 31, 2022. A bibliometric analysis of acupuncture for stroke was conducted by CiteSpace (6.2.R4) and VOSviewer (1.6.17). In this study, VOSviewer was used for visual analysis of countries, institutions, authors, journals, keywords, and co-cited references. CiteSpace was used to draw a keyword burst map and a co-cited reference burst map. A total of 534 papers were obtained from the Web of Science Core Collection. The number of papers per year showed a rapid upward trend. The most productive country and institution in this field were China (452) and the Fujian University of Traditional Chinese Medicine (43), respectively. Tao Jing had the highest number of articles (34), and EZ Longa was the most popular author (129 co-citations). Neural Regeneration Research (51) was the most productive journal, and Stroke (1346) was the most co-cited journal. An paper written by EZ Longa was the most influential reference, with the highest citation count. The hotspots and frontiers of this area of research were focused on the mechanisms of acupuncture, especially its neural regenerative or neuroprotective effects. This study used CiteSpace and VOSviewer for bibliometric analysis to provide researchers with information on the research status, hotspots, and trends in acupuncture for stroke research over the past 26 years.
Subject(s)
Acupuncture Therapy , Medicine, East Asian Traditional , Stroke , Humans , Bibliometrics , China , Stroke/therapyABSTRACT
Epilepsy is a prevalent and severe neurological disorder and approximately 30% of patients are resistant to existing medications. It is of utmost importance to develop alternative therapies to treat epilepsy. Schisandrin B (SchB) is a major bioactive constituent of Schisandra chinensis (Turcz.) Baill and has multiple neuroprotective effects, sedative and hypnotic activities. In this study, we investigated the antiseizure effect of SchB in various mouse models of seizure and explored the underlying mechanisms. Pentylenetetrazole (PTZ), strychnine (STR), and pilocarpine-induced mouse seizure models were established. We showed that injection of SchB (10, 30, 60 mg/kg, i.p.) dose-dependently delayed the onset of generalized tonic-clonic seizures (GTCS), reduced the incidence of GTCS and mortality in PTZ and STR models. Meanwhile, injection of SchB (30 mg/kg, i.p.) exhibited therapeutic potential in pilocarpine-induced status epilepticus model, which was considered as a drug-resistant model. In whole-cell recording from CHO/HEK-239 cells stably expressing recombinant human GABAA receptors (GABAARs) and glycine receptors (GlyRs) and cultured hippocampal neurons, co-application of SchB dose-dependently enhanced GABA or glycine-induced current with EC50 values at around 5 µM, and application of SchB (10 µM) alone did not activate the channels in the absence of GABA or glycine. Furthermore, SchB (10 µM) eliminated both PTZ-induced inhibition on GABA-induced current (IGABA) and strychnine (STR)-induced inhibition on glycine-induced current (Iglycine). Moreover, SchB (10 µM) efficiently rescued the impaired GABAARs associated with genetic epilepsies. In addition, the homologous mutants in both GlyRs-α1(S267Q) and GABAARs-α1(S297Q)ß2(N289S)γ2L receptors by site-directed mutagenesis tests abolished SchB-induced potentiation of IGABA and Iglycine. In conclusion, we have identified SchB as a natural positive allosteric modulator of GABAARs and GlyRs, supporting its potential as alternative therapies for epilepsy.
Subject(s)
Epilepsy , Lignans , Polycyclic Compounds , Receptors, Glycine , Mice , Animals , Humans , Pilocarpine/adverse effects , Strychnine/pharmacology , Strychnine/therapeutic use , Seizures/chemically induced , Seizures/drug therapy , Receptors, GABA-A , Glycine/pharmacology , Hypnotics and Sedatives , gamma-Aminobutyric Acid , CyclooctanesABSTRACT
BACKGROUND: For many years, the role of the microbiome in tumor progression, particularly the tumor microbiome, was largely overlooked. The connection between the tumor microbiome and the tumor genome still requires further investigation. METHODS: The TCGA microbiome and genome data were obtained from Haziza et al.'s article and UCSC Xena database, respectively. Separate WGCNA networks were constructed for the tumor microbiome and genomic data after filtering the datasets. Correlation analysis between the microbial and mRNA modules was conducted to identify oncogenome associated microbiome module (OAM) modules, with three microbial modules selected for each tumor type. Reactome analysis was used to enrich biological processes. Machine learning techniques were implemented to explore the tumor type-specific enrichment and prognostic value of OAM, as well as the ability of the tumor microbiome to differentiate TP53 mutations. RESULTS: We constructed a total of 182 tumor microbiome and 570 mRNA WGCNA modules. Our results show that there is a correlation between tumor microbiome and tumor genome. Gene enrichment analysis results suggest that the genes in the mRNA module with the highest correlation with the tumor microbiome group are mainly enriched in infection, transcriptional regulation by TP53 and antigen presentation. The correlation analysis of OAM with CD8+ T cells or TAM1 cells suggests the existence of many microbiota that may be involved in tumor immune suppression or promotion, such as Williamsia in breast cancer, Biostraticola in stomach cancer, Megasphaera in cervical cancer and Lottiidibacillus in ovarian cancer. In addition, the results show that the microbiome-genome prognostic model has good predictive value for short-term prognosis. The analysis of tumor TP53 mutations shows that tumor microbiota has a certain ability to distinguish TP53 mutations, with an AUROC value of 0.755. The tumor microbiota with high importance scores are Corallococcus, Bacillus and Saezia. Finally, we identified a potential anti-cancer microbiota, Tissierella, which has been shown to be associated with improved prognosis in tumors including breast cancer, lung adenocarcinoma and gastric cancer. CONCLUSION: There is an association between the tumor microbiome and the tumor genome, and the existence of this association is not accidental and could change the landscape of tumor research.
Subject(s)
Breast Neoplasms , Ovarian Neoplasms , Female , Humans , Prognosis , Gene Regulatory Networks , Breast Neoplasms/genetics , Breast Neoplasms/pathology , RNA, MessengerABSTRACT
Pancreatic cancer is a high mortality malignancy with almost equal mortality and morbidity rates. Both normal and tumour tissues of the pancreas were previously considered sterile. In recent years, with the development of technologies for high-throughput sequencing, a variety of studies have revealed that pancreatic cancer tissues contain small amounts of bacteria and fungi. The intratumour microbiome is being revealed as an influential contributor to carcinogenesis. The intratumour microbiome has been identified as a crucial factor for pancreatic cancer progression, diagnosis, and treatment, chemotherapy resistance, and immune response. A better understanding of the biology of the intratumour microbiome of pancreatic cancer contributes to the establishment of better early cancer screening and treatment strategies. This review focuses on the possible origins of the intratumour microbiome in pancreatic cancer, the intratumour localization, the interaction with the tumour microenvironment, and strategies for improving the outcome of pancreatic cancer treatment. Thus, this review offers new perspectives for improving the prognosis of pancreatic cancer.
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Research on the relationship between the microbiome and cancer has been controversial for centuries. Recent works have discovered that the intratumor microbiome is an important component of the tumor microenvironment (TME). Intratumor bacteria, the most studied intratumor microbiome, are mainly localized in tumor cells and immune cells. As the largest bacterial reservoir in human body, the gut microbiome may be one of the sources of the intratumor microbiome in gastrointestinal malignancies. An increasing number of studies have shown that the gut and intratumor microbiome play an important role in regulating the immune tone of tumors. Moreover, it has been recently proposed that the gut and intratumor microbiome can influence tumor progression by modulating host metabolism and the immune and immune tone of the TME, which is defined as the immuno-oncology-microbiome (IOM) axis. The proposal of the IOM axis provides a new target for the tumor microbiome and tumor immunity. This review aims to reveal the mechanism and progress of the gut and intratumor microbiome in gastrointestinal malignancies such as esophageal cancer, gastric cancer, liver cancer, colorectal cancer and pancreatic cancer by exploring the IOM axis. Providing new insights into the research related to gastrointestinal malignancies.
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OBJECTIVE: To observe the effect of preoperative, intraoperative and postoperative electroacupuncture (EA) intervention on postoperative urination function in patients with mixed hemorrhoid surgery. METHODS: A total of 240 patients with mixed hemorrhoid surgery under lumbar anesthesia were randomly divided into an EA preconditioning group (group A, 60 cases, 9 cases dropped off), an intraoperative EA group (group B, 60 cases, 4 cases dropped off), a postoperative EA group (group C, 60 cases, 6 cases dropped off), and a non-acupuncture group (group D, 60 cases, 3 cases dropped off). In the groups A, B and C, EA was exerted at Zhongliao (BL 33) and Huiyang (BL 35) , with disperse-dense wave, 4 Hz/20 Hz in frequency, and lasting 30 min, at 30 min before lumbar anesthesia, immediately after lumbar anesthesia and 6 h after surgery, respectively. No EA intervention was performed in the group D. The postoperative urination smoothness score in each group was observed 24 h after surgery. The first urination time, first urination volume, urine residual volume after first urination were recorded, and incidence of indwelling catheterization, postoperative visual analogue scale (VAS) score, number of remedial analgesia, and the incidence of postoperative nausea and vomiting were observed in each group. RESULTS: In the groups A, B and C, the postoperative urination smoothness scores were superior to the group D (P<0.05), and the time of first urination was earlier than the group D (P<0.05). In the group C, the time of first urination was earlier than the group A and the group B (P<0.05), the first urination volume was higher than the group D (P<0.05), and the urine residual volume after first urination was lower than the group D (P<0.05). There was no significant difference in the incidence of indwelling catheterization and postoperative nausea and vomiting among the 4 groups (P>0.05). The VAS scores of the group A, B and C were lower than that in the group D (P<0.05), and the number of remedial analgesia cases was lower than that in the group D (P<0.05). CONCLUSION: EA intervention could promote the recovery of urination function and relieve postoperative pain in patients with mixed hemorrhoids surgery. Early postoperative EA intervention is more conducive to the recovery of urination function.
Subject(s)
Electroacupuncture , Hemorrhoids , Humans , Hemorrhoids/surgery , Urination , Postoperative Nausea and Vomiting , Acupuncture PointsABSTRACT
Purpose: This paper presents a preliminary study on whether repetitive transcranial magnetic stimulation (rTMS) can modulate the nutritional status of persistent vegetative state (PVS) patients (the primary endpoint) by regulating the intestinal flora and the metabolites, with the correlation between them also investigated. Methods: Seventy-six patients with PVS were selected and divided into the observation group (n = 38) and the control group (n = 38) by random numerical grouping. All subjects' stool samples were examined for metabolites and analyzed regarding the short-chain fatty acids (SCFAs) content. All subjects' serum albumin, prealbumin, and hemoglobin levels were measured before and after the treatment. Nutrition risk screening 2002 was performed on all the subjects before and after the treatment and on the 30th and 90th days of the follow-up. Results: (1) Intestinal flora structure: the Chao index, Ace index, and Shannon index of the observation group and the control group were significantly higher (p < 0.05), while the Simpson index was significantly lower (p < 0.05) following the treatment. (2) Metabolites of the intestinal flora: the observation group had significantly higher levels of acetic acid, butyric acid, and valeric acid (p < 0.05), as well as lower levels of propionic acid (p < 0.05) following the treatment. (3) Nutritional status (the primary endpoint): following the treatment, the above serum nutritional indices were significantly higher in both groups (p < 0.05), while the indices of the observation group were significantly higher than those of the control group (p < 0.05). Conclusion: The rTMS method may improve the nutritional status of patients with PVS by regulating the structure of the intestinal flora and affecting the level of SCFAs through the microbiota-gut-brain axis. The possible mechanism involves how high-frequency rTMS can cause increased excitation in the frontal lobe of the right side of the brain, thus regulating the 5-hydroxytryptamine and norepinephrine levels.
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OBJECTIVE: To estimate the minimal clinically important difference (MCID) of the frequency of bowel movement for the patients with chronic severe functional constipation treated with acupuncture so as to provide the evidence for the clinical decision. METHODS: In this study, 813 patients with chronic severe functional constipation treated with acupuncture in two previous randomized controlled trials were included. Through the anchor-based method (anchored by the item 28 "satisfaction with previous treatment" of the patient assessment of constipation-quality of life [PAC-QOL]) and the distribution-based method, the MCID of the weekly frequency of complete spontaneous bowel movement (CSBM) and spontaneous bowel movement (SBM) was analyzed statistically in the patients. RESULTS: The MCID of the mean weekly frequency of CSBM and SBM was 1.3 times and 1.6 times in patients with chronic severe functional constipation treated with acupuncture, respectively. CONCLUSION: The mean increase of the weekly CSMB is ≥ 1.3 times and that of SBM is ≥ 1.6 times after treatment when compared with the baseline respectively, suggesting the clinical significance.
Subject(s)
Acupuncture Therapy , Quality of Life , Humans , Minimal Clinically Important Difference , Treatment Outcome , Constipation/therapyABSTRACT
Hepatitis B virus (HBV) infection is still a serious public health problem worldwide. Antiviral therapies such as interferon and nucleos(t)ide analogs efficiently control HBV replication, but they cannot eradicate chronic hepatitis B (CHB) because of their incapacity to eliminate endocellular covalently closed circular DNA (cccDNA). Thus, there is a necessity to develop new strategies for targeting cccDNA. As cccDNA is difficult to clear, transcriptional silencing of cccDNA is a possible effective strategy. HBx plays a vitally important role in maintaining the transcriptional activity of cccDNA and it could be a target for blocking the transcription of cccDNA. To screen new drugs that may contribute to antiviral therapy, the ability of 2,000 small-molecule compounds to inhibit HBx was examined by the HiBiT lytic detection system. We found that the macrolide compound rapamycin, which is clinically used to prevent acute rejection after organ transplantation, could significantly reduce HBx protein expression. Mechanistic studies demonstrated that rapamycin decreased the stability of the HBx protein by promoting its degradation via the ubiquitin-proteasome system. Moreover, rapamycin inhibited HBV RNA, HBV DNA, and cccDNA transcription levels in HBV-infected cells. In addition, HBx deficiency abrogated the inhibition of cccDNA transcription induced by rapamycin. Similar results were also confirmed in a recombinant cccDNA mouse model. In summary, we report a new small-molecule, rapamycin, which targets HBx to block HBV cccDNA transcription and inhibit HBV replication. This approach can identify new strategies to cure CHB.
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HBV is strongly associated with HCC development and DEAD-box RNA helicase 17 (DDX17) is a very important member of the DEAD box family that plays key roles in HCC development by promoting cancer metastasis. However, the important role of DDX17 in the pathogenesis of HBV-related HCC remains unclear. In this study, we investigated the role of DDX17 in the replication of HBV and the development of HBV-associated HCC. Based on data from the GEO database and HBV-infected cells, we found that DDX17 was upregulated by the HBV viral protein X (HBx). Mechanistically, increased DDX17 expression promoted HBV replication and transcription by upregulating ZWINT. Further study showed that DDX17 could promote HBx-mediated HCC metastasis. Finally, the promotive effect of DDX17 on HBV and HBV-related HCC was confirmed in vivo. In summary, the results revealed the novel role of DDX17 in the replication of HBV and the metastasis of HBV-associated HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Carcinogenesis , Carcinoma, Hepatocellular/etiology , Cell Transformation, Neoplastic , DEAD-box RNA Helicases/genetics , Hepatitis B virus , Humans , Liver Neoplasms/etiologyABSTRACT
Current anti-HBV therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure, inducing hepatitis B surface antigen (HBsAg) loss in very few patients. Notably, the level of HBsAg has been established as an accurate indicator to evaluate the drug efficacy and predict the disease prognosis, thus exploring a novel drug targeting HBsAg will be of great significance. Herein, by screening 978 compounds from an FDA-approved drug library and determining the inhibitory function of each drug on HBsAg level in HepG2.2.15 cells supernatant, we identified that pimobendan (Pim) has a powerful antiviral activity with relatively low cytotoxicity. The inhibitory effect of Pim on HBsAg as well as other HBV markers was validated in HBV-infected cell models and HBV-transgenic mice. Mechanistically, real-time PCR and dual-luciferase reporter assay were applied to identify the partial correlation of transcription factor CAAT enhancer-binding protein α (C/EBPα) with the cccDNA transcription regulated by Pim. This indicates Pim is an inhibitor of HBV transcription through suppressing HBV promoters to reduce HBV RNAs levels and HBsAg production. In conclusion, Pim was identified to be a transcription inhibitor of cccDNA, thereby inhibiting HBsAg and other HBV replicative intermediates both in vitro and in vivo. This report may provide a promising lead for the development of new anti-HBV agent.
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BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is a global public health problem and one of the leading causes of all-cause mortality. However, the pathogenic mechanisms and intervention methods for CKD progression are not fully understood. EXPERIMENTAL APPROACH: Plasma from patients with uraemia and from healthy controls (n = 30 per group) was analysed with LC-MS/MS-based non-targeted metabolomics to identify potential markers of uraemia. These potential markers were validated in the same cohort and a second cohort (n = 195) by quantitative analysis of the markers, using LC-MS/MS. The most promising marker was identified by correlation analysis and further validated using HK-2 cells and mouse models. KEY RESULTS: Trimethylamine N-oxide (TMAO) was identified as a promising marker among the 18 potential markers found in the first cohort, and it was optimally correlated with renal function of CKD patients in the second cohort. Treatment of HK-2 cells with TMAO decreased cell viability and up-regulated expression of α-smooth muscle actin. In mice, a TMAO-containing diet decreased kidney mass and increased protein expression of α-smooth muscle actin. Also, control of TMAO production by inhibiting its biosynthetic pathway with 3,3-dimethyl-1-butanol or disrupting gut microbiota function with an antibiotic cocktail, attenuated renal injury in a murine model of CKD. CONCLUSION AND IMPLICATIONS: Our data show that decreased TMAO production could be a new strategy to attenuate the progression of renal injury in CKD.
Subject(s)
Renal Insufficiency, Chronic , Uremia , Actins , Animals , Biomarkers , Chromatography, Liquid , Humans , Methylamines/metabolism , Mice , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/metabolism , Tandem Mass SpectrometryABSTRACT
Two new diterpenoids, dauricumins A (1) and B (2), together with two known aromatic meroterpenoids (3 and 4), were isolated from the petroleum ether soluble fraction of the stems from Rhododendron dauricum through an HPLC-MS-SPE-NMR combination strategy. The absolute configurations of 1 and 2 were elucidated by ECD calculations and [Rh2 (OCOCF3)4]-induced CD spectrum analysis. In a membrane potential FLIPR assay, confluentin (4) showed an agonistic effect on GABAA receptor (EC50 = 20 µM).
Subject(s)
Diterpenes , Rhododendron , Diterpenes/chemistry , Diterpenes/pharmacology , GABA-A Receptor Agonists , Molecular Structure , Receptors, GABA-A , Rhododendron/chemistryABSTRACT
OBJECTIVE: To observe the clinical therapeutic effect on mild and moderate postpartum depression treated with acupuncture of Tiaoren Tongdu (regulating the conception vessel and unblocking the governor vessel) on the base of real world. METHODS: A total of 116 patients with mild and moderate postpartum depression were divided into an acupuncture group (103 cases) and a non-acupuncture group (13 cases) according to treatment regimen provided. In the acupuncture group, acupuncture of Tiaoren Tongdu was applied to Baihui (GV 20), Yintang (GV 29), Zhongwan (CV 12), Qihai (CV 6), Guanyuan (CV 4), Neiguan (PC 6), Shenmen (HT 7), Hegu (LI 4), Zusanli (ST 36), Sanyinjiao (SP 6) and Taichong (LR 3). Needles were retained for 30 min each time, the treatment was given once every other day, 3 times a week. In the non-acupuncture group, psychotherapy was provided, once daily. The duration of treatment in the two groups was 8 weeks. According to the treatment times of acupuncture, the acupuncture group was subdivided into an acupuncture A group (60 cases with total treatments ≥ 6 times) and an acupuncture B group (43 cases with total treatments<6 times). Using propensity score matching method, the patients of the acupuncture A and B groups were matched each other. Finally, 31 pairs of cases were matched successfully. Before treatment, at 1st, 2nd, 4th and 8th weeks of treatment, as well as at 3-month follow-up, the scores of Hamilton depression scale (HAMD) were compared in patients among the three groups. Using Logistic regression, the impact of acupuncture frequencies on the therapeutic effect was analyzed and the clinical therapeutic effect was assessed. RESULTS: The total effective rate of the acupuncture A group was 100.0% (31/31), better than 76.9% (10/13) in the non-acupuncture group and 58.1% in the acupuncture B group (18/31) (P<0.05). HAMD score at each time point after treatment was lower than that before treatment in the patients of each group (P<0.05). But HAMD score at each time point after treatment in either the acupuncture A group or the acupuncture B group was lower than that in the non-acupuncture group separately (P<0.05), HAMD scores in the acupuncture A group at the 4th and 8th weeks of treatment and at follow-up were lower than those in the acupuncture B group (P<0.05). Logistic regression analysis showed that the total times of acupuncture treatment and the persistent days of treatment had a certain relation to therapeutic effect (P<0.05). CONCLUSION: Acupuncture of Tiaoren Tongdu effectively improves in mild and moderate postpartum depression and its therapeutic effect is closely related to treatment course.
Subject(s)
Acupuncture Therapy , Depression, Postpartum , Acupuncture Points , Depression/therapy , Depression, Postpartum/therapy , Female , Humans , Needles , Treatment OutcomeABSTRACT
Chronic hepatitis B virus (HBV) infection is a significant public health burden worldwide. HBV covalently closed circular DNA (cccDNA) organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B (CHB). Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In the present study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. Silent mating type information regulation 2 homolog 7 (SIRT7), as an NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalyzed histone 3 lysine 122 (H3K122) desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase, suppressor of variegation 3-9 homolog 1 (SUV39H1) and SET domain containing 2 (SETD2) to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection.
Subject(s)
Catalysis , DNA, Circular/metabolism , Histone Methyltransferases/genetics , Histones/metabolism , Sirtuins/metabolism , DNA, Viral/genetics , Hepatitis B/prevention & control , Hepatitis B/therapy , Hepatitis B/virology , Hepatitis B virus/pathogenicity , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/prevention & control , Humans , Sirtuins/genetics , Transcription, Genetic/genetics , Virus Replication/geneticsABSTRACT
There has been a long history since human beings began to realize the existence of post-traumatic symptoms. Posttraumatic stress disorder (PTSD), a diagnostic category adopted in 1980 in the Diagnostic and Statistical Manual of Mental Disorders-â ¢, described typical clusters of psychiatric symptoms occurring after traumatic events. Abundant researches have helped deepen the understanding of PTSD in terms of epidemiological features, biological mechanisms, and treatment options. The prevalence of PTSD in general population ranged from 6.4% to 7.8% and was significantly higher among groups who underwent major public traumatic events. There has been a long way in the studies of animal models and genetic characteristics of PTSD. However, the high comorbidity with other stress-related psychiatric disorders and complexity in the pathogenesis of PTSD hindered the effort to find specific biological targets for PTSD. Neuroimage was widely used to elucidate the underlying neurophysiological mechanisms of PTSD. Functional MRI studies have showed that PTSD was linked to medial prefrontal cortex, anterior cingulate cortex and sub-cortical structures like amygdala and hippocampus, and to explore the functional connectivity among these brain areas which might reveal the possible neurobiological mechanism related to PTSD symptoms. For now, cognitive behavior therapy-based psychotherapy, including combination with adjunctive medication, showed evident treatment effects on PTSD. The emergence of more effective PTSD pharmacotherapies awaits novel biomarkers from further fundamental research. Several natural disasters and emergencies have inevitably increased the possibility of suffering from PTSD in the last two decades, making it critical to strengthen PTSD research in China. To boost PTSD study in China, the following suggestions might be helpful: (1) establishing a national psychological trauma recover project, and (2) exploring the mechanisms of PTSD with joint effort and strengthening the indigenized treatment of PTSD.
Subject(s)
Stress Disorders, Post-Traumatic , Animals , Brain , Comorbidity , Hippocampus , Humans , Magnetic Resonance Imaging , Stress Disorders, Post-Traumatic/epidemiology , Stress Disorders, Post-Traumatic/therapyABSTRACT
Hepatitis B virus (HBV) infection remains a major health problem worldwide. Sufficient maintenance of the HBV covalently closed circular DNA (cccDNA), which serves as a template for HBV transcription, is responsible for the failure of antiviral therapies. While accumulating evidence suggests that cccDNA transcription is regulated by epigenetic machinery, particularly the acetylation and methylation of cccDNA-bound histone 3 (H3) and histone 4 (H4), the potential contributions of histone succinylation and related host factors remain obscured. Here, by screening a series of succinyltransferases and desuccinylases, we identified KAT2A as an important host factor of HBV transcription and replication. By using HBV-infected cells and mouse models with HBV infection, KAT2A was found to affect the transcriptional activity of cccDNA but did not affect cccDNA production. Mechanism studies showed that KAT2A is mainly located in the nucleus and could bind to cccDNA through interaction with HBV core protein (HBc). Moreover, we confirmed histone H3K79 succinylation (H3K79succ) as a histone modification on cccDNA minichromosome by using the cccDNA ChIP-Seq approach. Importantly, KAT2A silencing specifically reduced the level of cccDNA-bound succinylated H3K79. In conclusion, KAT2A promotes HBV transcription and replication through epigenetic machinery, and our findings may provide new insight into the treatment of HBV infection.
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BACKGROUND & AIMS: Current antiviral therapies help keep HBV under control, but they are not curative, as they are unable to eliminate the intracellular viral replication intermediate termed covalently closed circular DNA (cccDNA). Therefore, there remains an urgent need to develop strategies to cure CHB. Functional silencing of cccDNA is a crucial curative strategy that may be achieved by targeting the viral protein HBx. METHODS: We screened 2,000 small-molecule compounds for their ability to inhibit HiBiT-tagged HBx (HiBiT-HBx) expression by using a HiBiT lytic detection system. The antiviral activity of a candidate compound and underlying mechanism of its effect on cccDNA transcription were evaluated in HBV-infected cells and a humanised liver mouse model. RESULTS: Dicoumarol, an inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), significantly reduced HBx expression. Moreover, dicoumarol showed potent antiviral activity against HBV RNAs, HBV DNA, HBsAg and HBc protein in HBV-infected cells and a humanised liver mouse model. Mechanistic studies demonstrated that endogenous NQO1 binds to and protects HBx protein from 20S proteasome-mediated degradation. NQO1 knockdown or dicoumarol treatment significantly reduced the recruitment of HBx to cccDNA and inhibited the transcriptional activity of cccDNA, which was associated with the establishment of a repressive chromatin state. The absence of HBx markedly blocked the antiviral effect induced by NQO1 knockdown or dicoumarol treatment in HBV-infected cells. CONCLUSIONS: Herein, we report on a novel small molecule that targets HBx to combat chronic HBV infection; we also reveal that NQO1 has a role in HBV replication through the regulation of HBx protein stability. LAY SUMMARY: Current antiviral therapies for hepatitis B are not curative because of their inability to eliminate covalently closed circular DNA (cccDNA), which persists in the nuclei of infected cells. HBV X (HBx) protein has an important role in regulating cccDNA transcription. Thus, targeting HBx to silence cccDNA transcription could be an important curative strategy. We identified that the small molecule dicoumarol could block cccDNA transcription by promoting HBx degradation; this is a promising therapeutic strategy for the treatment of chronic hepatitis B.