Efficacy of botulinum toxin A combined with extracorporeal shockwave therapy in post-stroke spasticity: a systematic review.

Objectives: In recent years, there has been an increase in the number of randomized clinical trials of BTX-A combined with ESWT for the treatment of post-stroke spasticity. This has made it possible to observe the benefits of combination therapy in clinical practice. Therefore, this paper reviews the effectiveness of BTX-A in combination with ESWT for the treatment of post-stroke spasticity. Methods: By October 2023, a systematic review was conducted in the databases PubMed, Cochrane, Embase, Medline, Web of Science, China National Knowledge Infrastructure, Wan Fang Database, China Biology Medicine disc and China Science and Technology Journal Database were systematically searched. We included randomized controlled trials that reported outcome metrics such as MAS, FMA, and MBI score. Studies were excluded if MAS was not reported. The quality of the included studies was assessed by the Cochrane Collaboration's tool for assessing risk of bias, and the AMSTAR quality rating scale was selected for self-assessment. Results: A total of 70 articles were included in the initial search, and six were ultimately included. The results of the included studies showed that the combination therapy was effective in reducing MAS scores and improving FMA and MBI scores in patients with spasticity compared to the control group. Combination therapy has also been shown to improve joint mobility and reduce pain in spastic limbs. Conclusion: Cumulative evidence from clinical randomized controlled trial studies suggests that the combination therapy is effective in reducing lower limb spasticity and improving mobility after stroke. However, more clinical trials are still needed to corroborate the evidence regarding the efficacy of BTX-A combined with shockwave therapy. Systematic Review Registration: The system review can be searched in the PROSPERO database (CRD42023476654).

Health-related quality of life in Chinese SLE patients: evidence from 1568 SLE patients and 2610 healthy controls.

OBJECTIVE: To investigate the effects of systemic lupus erythematosus (SLE) on health-related quality of life (HRQOL), the relationship between disease activity and HRQOL, and potential factors affecting HRQOL in Chinese SLE patients. METHODS: This study recruited 1568 patients and 2610 controls to explore the effects of SLE on HRQOL. The association between disease activity and HRQOL, and the influencing factors of HRQOL were determined in 1568 patients. Then, we prospectively followed 1096 patients to explore the association between reduced disease activity and improved HRQOL, and the influencing factors of improved HRQOL. The Short-Form 36 (SF-36) and SLE disease activity index (SLEDAI) were used to evaluate HRQOL and disease activity. RESULTS: Chinese SLE patients had lower HRQOL than controls in all domains (P < 0.001), especially in role-physical (RP) and role-emotional (RE). Compared with SLE patients from outside China, the HRQOL of Chinese patients appeared to be higher in mental component summary (MCS) but lower in RP and RE. SLEDAI was negatively correlated with HRQOL, which was validated using the results of a follow-up study, where SLEDAI reduction was positively associated with HRQOL improvements (P < 0.05). Furthermore, personality, life nervous and experiences of adverse life events may influence HRQOL and HRQOL improvements. CONCLUSION: SLE significantly affected the HRQOL of Chinese patients, especially in RP and RE. Disease activity was negatively correlated with HRQOL. We also found for the first time some factors affecting HRQOL, which can be regarded as the basis for improving the HRQOL of SLE patients.

Associations of RPEL1 and miR-1307 gene polymorphisms with disease susceptibility, glucocorticoid efficacy, anxiety, depression, and health-related quality of life in Chinese systemic lupus erythematosus patients.

OBJECTIVE: Our present study intended to examine the associations of RPEL1 and miR-1307 gene polymorphisms (rs4917385 and rs7911488) with susceptibility, glucocorticoids (GCs) efficacy, anxiety, depression, and health-related quality of life (HRQoL) in Chinese systemic lupus erythematosus (SLE) patients. METHODS: Initially, 1000 participants (500 SLE cases and 500 controls) were recruited for the case-control study. Then, 429 cases who received GCs were followed through 12 weeks to explore GCs efficacy, depression, anxiety, and HRQoL. We selected the iMLDR technique for genotyping: RPEL1: rs4917385 (G/T) and miR-1307: rs7911488 (A/G). RESULTS: The minor G allele of rs7911488 reduced the risk of SLE (p = .024). Four haplotypes consisting of rs4917385 and rs7911488 were associated with SLE susceptibility (p < .025). Both rs4917385 and rs7911488 were associated with anxiety symptoms and physical function (PF) in SLE patients (p < .025). The rs4917385 was associated with depression and its improvement. No statistical significance was found between RPEL1 and miR-1307 gene polymorphisms with GCs efficacy. Meanwhile, additive interaction analysis showed a significant association between RPEL1 and miR-1307 gene polymorphisms with tea consumption in anxiety. CONCLUSION: RPEL1 and miR-1307 gene polymorphisms (rs4917385 and rs7911488) might be related to SLE susceptibility in Chinese population. Additionally, the two polymorphisms were possibly associated with depression, anxiety, and HRQoL in Chinese SLE population.

An association study on the risk, glucocorticoids effectiveness, and prognosis of systemic lupus erythematosus: insight from mitochondrial DNA copy number.

This study aimed to explore the role of mitochondrial DNA copy number (mtDNAcn) in the risk, glucocorticoid (GC) effectiveness, and prognosis of systemic lupus erythematosus (SLE) and its interactions with environmental factors and tumor necrosis factor receptor-associated protein 1 (TRAP1) genetic polymorphisms. We first conducted a case-control study of 1198 subjects (595 SLE patients and 603 healthy controls). Subsequently, we followed up with patients to assess the effectiveness of GC treatment and the prognosis of SLE. Real-time fluorescent quantitative PCR (qPCR) was used to quantify mtDNAcn. Associations were estimated using logistic regression, and prognosis analysis was performed using Kaplan-Meier analysis and Cox proportional hazards models. Interactions on multiplicative and additive scales were also evaluated. Individuals with low mtDNAcn had an increased risk of SLE (P < 0.001). Low mtDNAcn was associated with poor GC effectiveness in patients with spicy food consumption or with arthritis (P < 0.05). mtDNAcn was significantly related to the prognosis of SLE in the drinking subgroup (P = 0.018). Furthermore, we found significant interactions between mtDNAcn and environmental factors/TRAP1 genetic polymorphisms on the risk, GC effectiveness, and prognosis of SLE. Our data suggest that low mtDNAcn is associated with an increased risk of SLE. Alteration of mtDNAcn may be associated with GC effectiveness and prognosis in certain subgroups of SLE. The interactions between mtDNAcn, environmental factors, and TRAP1 gene polymorphisms may jointly affect the risk, GC effectiveness, and prognosis of SLE.

[Pattern evolution and impact factor of Jiuduansha Wetland at the Yangtze Estuary during 1989-2020]. / 1989­2020å¹´é•¿æ±Ÿå£ä¹æ®µæ²™æ¹¿åœ°æ ¼å±€æ¼”å˜åŠå½±å“å› ç´ .

Affected by the changes of drainage basin and marine environment and human activities, estuarine wetland is fragile, sensitive, and complex in evolution. Jiuduansha Wetland is the largest estuarine shoal wetland in the Yangtze Estuary, and is undergoing rapid changes due to the reduction of sediment inputs and the invasion of alien species Spartina alterniflora. In this study, the changes of Jiuduansha Wetland from 1989 to 2020 were analyzed through remote sensing interpretation, field investigation, and topographic data analysis. The impacts of watershed sediment reduction and S. alterniflora invasion on Jiuduansha Wetland were analyzed based on the hydrological data of Datong station and the invasion history of S. alterniflora. The results showed that the total area of Jiuduansha Wetland (above -5 m) first increased and then decreased since 1991, reaching its maximum in 2005 (421.16 km2). The area of tidal flat wetland (above 0 m) and wetland vegetation increased continuously from 1989 to 2020, with 1.5 times and 47.1 times increases, respectively. The decreases of sediment supply led to a decrease in the total area of Jiuduansha Wetland (above -5 m) and a decrease growth rate of tidal flat wetland area above 0 m and vege-tation area. The invasive species S. alterniflora had expanded rapidly, occupied the space of native species, and became the dominant species in Jiuduansha Wetland since it was introduced in 1997. Sediment reduction and S. alterniflora invasion had led to the rapid changes of Jiuduansha Wetland structure. In order to avoid the degradation of ecological service, wetland protection and restoration should be taken to maintain the stability and health of Jiu-duansha Wetland.

Polycystic ovary syndrome and the risk of endometrial, ovarian and breast cancer: An updated meta-analysis.

BACKGROUND AND AIMS: This updated meta-analysis aimed to further quantify the risk of endometrial, ovarian, and breast cancer in patients with polycystic ovary syndrome (PCOS), thus providing updated and more reliable estimates. METHODS AND RESULTS: We identified relevant articles by searching electronic databases of PubMed, Embase, Web of Science, and Chinese Biological Medical Literature (CBM) published up to March 20, 2021. The pooled effect estimates and their 95% confidence intervals (CIs) were calculated using the random-effect model or the fixed-effect model. A total of 26 eligible studies were included. We found that PCOS was significantly associated with endometrial cancer (odds ratios [OR]: 3.66, 95%CI: 2.05-6.54, P < 0.001), but not with ovarian or breast cancer (OR: 1.23, 95%CI: 0.99-1.53, P = 0.059; OR: 0.94, 95%CI: 0.78-1.14, P = 0.551, respectively). However, in subgroups of high-quality studies, cohort studies, younger women (54 years or less or premenopausal), and studies with unadjusted body mass index (BMI), PCOS patients had a significantly higher risk of ovarian cancer. CONCLUSION: These results indicated that PCOS is a significant risk factor for endometrial cancer independent of BMI, but not for breast cancer. PCOS may increase the risk of ovarian cancer in younger women.

Mitochondrial DNA genetic variants are associated with systemic lupus erythematosus susceptibility, glucocorticoids efficacy and prognosis.

OBJECTIVE: To investigate the associations of mitochondrial DNA (mtDNA) genetic variants with SLE susceptibility, glucocorticoid (GC) efficacy and prognosis. METHODS: Our study was done in two stages. First, we performed whole mitochondrial genome sequencing in 100 patients and 100 controls to initially screen potential mtDNA variants associated with disease and GC efficacy. Then, we validated the results in an independent set of samples. In total, 605 SLE patients and 604 normal controls were included in our two-stage study. A two-stage efficacy study was conducted in 512 patients treated with GCs for 12 weeks. We also explored the association between mtDNA variants and SLE prognosis. RESULTS: In the combined sample, four mtDNA variants (A4833G, T5108C, G14569A, CA514-515-) were associated with SLE susceptibility (all PBH < 0.05). We confirmed that T16362C was related to efficacy of GCs (PBH = 0.014). Significant associations were detected between T16362C and T16519C and the efficacy of GCs in females with SLE (PBH < 0.05). In the prognosis study, variants A4833G (PBH = 0.003) and G14569A (PBH = 9.744 × 10-4) substantially increased SLE relapse risk. Female patients harbouring variants T5108C and T16362C were more prone to relapse (PBH < 0.05). Haplotype analysis showed that haplogroup G was linked with SLE susceptibility (PBH = 0.001) and prognosis (PBH = 0.013). Moreover, mtDNA variant-environment interactions were observed. CONCLUSION: We identified novel mtDNA genetic variants that were associated with SLE susceptibility, GC efficacy, and prognosis. Interactions between mtDNA variants and environmental factors were related to SLE risk and GC efficacy. Our findings provide important information for future understanding of the occurrence and development of SLE.

Prognostic Significance of Relative Hyperglycemia after Percutaneous Coronary Intervention in Patients with and without Recognized Diabetes.

BACKGROUND: The research on the association between the relative glycemic level postpercutaneous coronary intervention (PCI) and adverse prognosis in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients is relatively inadequate. OBJECTIVE: The study aimed to identify whether the glycemic level post-PCI predicts adverse prognosis in NSTE-ACS patients. METHODS: Patients (n=2465) admitted with NSTE-ACS who underwent PCI were enrolled. The relative glycemic level post-procedure was calculated as blood glucose level post-PCI divided by HbA1c level, which was named post-procedural glycemic index (PGI). The primary observational outcome of this study was major adverse cardiovascular events (MACE) [defined as a composite of all-cause death, non-fatal myocardial infarction (MI) and any revascularization]. RESULTS: The association between PGI and MACE rate is presented as a U-shape curve. Higher PGIs [hazard ratio (HR): 1.669 (95% confidence interval (CI): 1.244-2.238) for the third quartile (Q3) and 2.076 (1.566-2.753) for the fourth quartile (Q4), p<0.001], adjusted for confounding factors, were considered to be one of the independent predictors of MACE. The association between the PGI and the risk of MACE was more prominent in the non-diabetic population [HR (95%CI) of 2.356 (1.456-3.812) for Q3 and 3.628 (2.265-5.812) for Q4, p<0.001]. There were no significant differences in MACE risk between PGI groups in the diabetic population. CONCLUSION: Higher PGI was a significant and independent predictor of MACE in NSTE-ACS patients treated with PCI. The prognostic effect of the PGI is more remarkable in subsets without pre-existing diabetes than in the overall population. The predictive value of PGI was not identified in the subgroup with diabetes.

Triglyceride-Glucose Index as a Surrogate Marker of Insulin Resistance for Predicting Cardiovascular Outcomes in Nondiabetic Patients with Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

AIM: The triglyceride-glucose index (TyG index) is proposed as a surrogate parameter for insulin resistance (IR) and, when elevated, is related to increased cardiovascular risks. Whether the TyG index is of great value in predicting adverse prognosis for individuals diagnosed with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), who received elective percutaneous coronary intervention (PCI), and without recognized diabetes remains unclear. METHODS: Overall, 1,510 subjects diagnosed with NSTE-ACS, who received elective PCI, and without recognized diabetes were enrolled in the current study. All participants received a routine follow-up after discharge. The TyG index was obtained from the following equation: napierian logarithmic (ln) [fasting triglyceride (TG, mg/dL)×fasting blood glucose (FBG, mg/dL)/2]. Adverse cardiovascular events included all-cause death, nonfatal myocardial infarction (MI), nonfatal ischemic stroke, and ischemia-driven revascularization, composite of which was defined as the primary endpoint. RESULTS: Overall, 316 (20.9%) endpoint events were documented during a 48-month follow-up. Despite adjusting for confounding variates, the TyG index remains to be a significant risk predictor for the primary endpoint, with a hazard ratio (HR) [95% confidence interval (CI)] of 2.433 (1.853-3.196) (P＜0.001). A significant enhancement on the predictive performance for the primary endpoint emerged when adding the TyG index into a baseline model [area under the receiver-operating characteristic (ROC) curve (AUC), 0.835 for baseline model vs. 0.853 for baseline model＋TyG index, P＜0.001; net reclassification improvement (NRI), 0.194, P＜0.001; integrated discrimination improvement (IDI), 0.023, P=0.007]. CONCLUSIONS: The TyG index is an independent risk predictor for adverse cardiovascular events in nondiabetic subjects diagnosed with NSTE-ACS and who received elective PCI. Further prospective studies are needed to verify these findings.

Relationship between monocyte/lymphocyte ratio and non-culprit plaque vulnerability in patients with acute coronary syndrome: An optical coherence tomography study.

The importance of monocyte/lymphocyte ratio (MLR) has been indicated in the initiation and progression of coronary artery disease. However, few previous researches demonstrated the relationship between MLR and plaque vulnerability. We aimed to investigate coronary non-culprit plaque vulnerability in patients with acute coronary syndrome (ACS) by optical coherence tomography (OCT).A total of 72 ACS patients who underwent coronary angiography and OCT test in Beijing Anzhen Hospital were included in this retrospective study. The plaque vulnerability and plaque morphology were assessed by OCT.The non-culprit plaque in high MLR group exhibited more vulnerable features, characterizing as thinner thickness of fibrous cap (P = .013), greater maximum lipid core angle (P = .010) and longer lipid plaque length (P = .041). A prominently negative liner relation was found between MLR and thickness of fibrous cap (R = -0.225, P = .005). Meanwhile, the proportion of OCT-detected thin cap fibro-atheroma (TCFA) (P = .014) and plaque rupture (P = .017) were higher in high MLR group. Most importantly, multivariable logistic regression analysis showed MLR level was identified as an independent contributor to the presence of TCFA (OR:3.316, 95%: 1.448-7.593, P = .005). MLR could differentiate TCFA with a sensitivity of 60.0% and a specificity of 85.1%.Circulating MLR level has potential value in identifying the presence of vulnerable plaque in patients with ACS. MLR, as a non- invasive biomarker of inflammation, may be valuable in revealing plaque vulnerability.

Prognostic impact of estimated remnant-like particle cholesterol in patients with differing glycometabolic status: an observational cohort study from China.

BACKGROUND: It is uncertain whether estimated remnant-like particle cholesterol (RLP-C) could predict residual risk in patients with different glycometabolic status. This study aimed to evaluate the relationship between estimated RLP-C and adverse prognosis in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) treated with percutaneous coronary intervention (PCI) and to identify the potential impact of glycometabolism on the predictive value of estimated RLP-C. METHODS: The study assessed 2419 participants with NSTE-ACS undergoing PCI at Beijing Anzhen Hospital from January to December 2015. Estimated RLP-C was calculated as follows: total cholesterol (TC) minus low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). The adverse events included all-cause death, non-fatal myocardial infarction (MI), and ischemia-driven revascularization. RESULTS: Estimated RLP-C was prominently associated with adverse prognosis in the total population [hazard ratio (HR) 1.291 per 1-SD increase, 95% confidence interval (CI) 1.119-1.490, P <  0.001], independent of confounding risk factors. However, subgroup analysis showed that increasing estimated RLP-C was related to a higher risk of adverse events in the diabetic population only [HR 1.385 per 1-SD increase, 95% CI 1.183-1.620, P <  0.001]. Estimated RLP-C failed to be a significant determinant of adverse prognosis in non-diabetic and pre-diabetic subgroups. The addition of estimated RLP-C to a baseline model including traditional risk factors enhanced the predictive performance both in total and diabetic populations. CONCLUSIONS: High estimated RLP-C level is a significant predictor for recurrent adverse events in patients with diabetes and NSTE-ACS treated with PCI.

Impacts of triglyceride-glucose index on prognosis of patients with type 2 diabetes mellitus and non-ST-segment elevation acute coronary syndrome: results from an observational cohort study in China.

BACKGROUND: The relationship between triglyceride-glucose index (TyG index) and the prevalence and prognosis of cardiovascular disease has been confirmed by former studies. However, it remains uncertain whether TyG index has a prognostic impact in patients with type 2 diabetes mellitus (T2DM) and non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). METHODS: The study retrospectively enrolled 798 patients (mean age: 60.9 ± 8.3 years; 68.3% men) with T2DM and NSTE-ACS who underwent PCI at Beijing Anzhen Hospital from January to December 2015. TyG index was calculated as previously reported: ln [fasting TGs (mg/dL) * FBG (mg/dL)/2]. The primary endpoint was a composite of adverse events as follows: all-cause death, non-fatal myocardial infarction (MI) and ischemia-driven revascularization. RESULTS: TyG index was significantly higher in patients with a primary endpoint event compared with those without. Multivariate Cox proportional hazards analysis showed that 1-unit increase of TyG index was independently associated with higher risk of primary endpoint, independent of other risk factors [hazard ratio (HR) 3.208 per 1-unit increase, 95% confidence interval (CI) 2.400-4.289, P < 0.001]. The addition of TyG index to a baseline risk model had an incremental effect on the predictive value for adverse prognosis [AUC: baseline risk model, 0.800 vs. baseline risk model + TyG index, 0.856, P for comparison < 0.001; category-free net reclassification improvement (NRI) 0.346, P < 0.001; integrated discrimination improvement (IDI) 0.087, P < 0.001]. CONCLUSIONS: Increased TyG index is a significant predictor of adverse prognosis in patients with T2DM and NSTE-ACS undergoing PCI. Further studies need to be performed to determine whether interventions for TyG index have a positive impact on improving clinical prognosis.

Impacts of geriatric nutritional risk index on prognosis of patients with non-ST-segment elevation acute coronary syndrome: Results from an observational cohort study in China.

BACKGROUND AND AIMS: It is recognized that malnutrition increases risk of worse prognosis in patients with various diseases. The present study investigated if poor nutritional status predicts adverse outcomes in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: The study enrolled 2299 patients (mean age: 60.01 ± 8.95 years; 71.8% male) with NSTE-ACS who underwent PCI at Beijing Anzhen Hospital from January to December 2015. The entire cohort was divided into training set (n = 1519) and testing set (n = 780) at a ratio of approximate 2 : 1. Nutritional status was assessed by geriatric nutritional risk index (GNRI). The primary endpoint was a composite of adverse events as follows: all-cause death, non-fatal myocardial infarction (MI) and any revascularization. Multivariate Cox analysis showed that GNRI significantly associated with primary endpoint, independent of other risk factors [hazard ratio (HR) 1.159 per 1-point decrease of GNRI, 95% confidence interval (CI) 1.130-1.189, p < 0.001]. The addition of GNRI to a baseline model had an incremental effect on the predictive value for adverse prognosis in training set [AUC: from 0.821 to 0.873, p < 0.001; category-free net reclassification improvement (NRI): 0.313, p < 0.001; integrated discrimination improvement (IDI): 0.108, p < 0.001]. The incremental effect of GNRI was further validated and confirmed in testing set. CONCLUSION: Lower GNRI is a significant predictor of adverse prognosis in patients with NSTE-ACS undergoing PCI. Further studies need to be performed to determine whether nutritional interventions have a positive impact on improving clinical prognosis.

Computational and experimental studies on copper-mediated selective cascade C-H/N-H annulation of electron-deficient acrylamide with arynes.

An efficient and convenient copper-mediated method has been developed to achieve direct cascade C-H/N-H annulation to synthesize 2-quinolinones from electron-deficient acrylamides and arynes. This method highlights an emerging but simple strategy to transform inert C-H bonds into versatile functional groups in organic synthesis to provide a new method of synthesizing 2-quinolinones efficiently. Mechanistic investigations by experimental and density functional theory (DFT) studies suggest that an organometallic C-H activation via a Cu(iii) intermediate is likely to be involved in the reaction.

Copper-Mediated Cascade C-H/N-H Annulation of Indolocarboxamides with Arynes: Construction of Tetracyclic Indoloquinoline Alkaloids.

An efficient and environmentally benign Cu-mediated method was developed for direct cascade C-H/N-H annulation to construct polyheterocyclic indoloquinoline scaffolds. This method highlights an emerging strategy for transforming inert C-H bonds into versatile functional groups in organic synthesis and provides a new versatile approach for the efficient synthesis of indolo[3,2-c] and [2,3-c]quinoline alkaloids.

Copper-Catalyzed Selective ortho-C-H/N-H Annulation of Benzamides with Arynes: Synthesis of Phenanthridinone Alkaloids.

An efficient and convenient copper-catalyzed method has been developed to achieve direct ortho-C-H/N-H annulation to synthesize phenanthridinones with arynes. This method highlights an emerging strategy to transform inert C-H bonds into versatile functional groups in organic synthesis and provides a new way to synthesize phenanthridinone alkaloids efficiently.

Palladium-catalyzed direct intermolecular silylation of remote unactivated C(sp3)-H bonds.

An efficient and convenient method has been developed to achieve direct silylation of unactivated remote primary or secondary C(sp3)-H bonds to form C-Si bonds with hexamethyldisilane (HMDS). This method highlights the emerging strategy to transform unactivated methyl or methylene into versatile functional groups in organic synthesis and provides a new method to construct functionalized C-Si bonds for synthetic chemistry.

Irbesartan, an FDA approved drug for hypertension and diabetic nephropathy, is a potent inhibitor for hepatitis B virus entry by disturbing Na(+)-dependent taurocholate cotransporting polypeptide activity.

The liver-specific Na(+)-dependent taurocholate cotransporting polypeptide (NTCP) was recently identified as an entry receptor for hepatitis B virus (HBV) hepatotropic infection. In this study, an NTCP-overexpressing HepG2 cell line named HepG2.N9 susceptible to HBV infection was established using transcription activator-like effector nucleases (TALEN) technology. Using this cell line, irbesartan, the new NTCP-interfering molecule reported recently, was demonstrated here to effectively inhibit HBV infection with an IC50 of 3.3µM for hepatitis B e antigen (HBeAg) expression and exhibited no obvious cytotoxicity up to 1000µM. Irbesartan suppressed HBV uptake weakly but inhibited HBV covalently closed circular DNA (cccDNA) formation efficiently at physiological temperature. These results suggested that irbesartan targeted HBV infection at a post-uptake prior to cccDNA formation step such as the cell membrane fusion. Based on these findings, irbesartan, an FDA approved drug for hypertension and diabetic nephropathy, could be a potential candidate for treatment of HBV infection although further in vivo experiments are required.

CpG oligodeoxynucleotide inhibits HBV replication in a hydrodynamic injection murine model.

BACKGROUND: Chronic HBV infection is a significant public health problem and one major cause of liver cirrhosis and hepatocellular carcinoma (HCC). HBV impairs the host immune system and results in immunotolerance, which is a major obstacle to HBV therapy. CpG oligodeoxynucleotide (ODN) is a strong immunostimulant which activates the innate immune response rapidly and has been shown to be an efficient therapy agent in viral infection treatment. Here, we report the anti-HBV activity of CpG-1826 in a hydrodynamic injection murine model. METHODS: CpG-1826 was administrated intraperitoneally every other day in HBV carrier mice established by tail vein hydrodynamic injection of HBV plasmids. The serum concentrations of HBV surface antigen (HBsAg), HBV e antigen (HBeAg), HBV surface antibody (HBsAb), HBV core antibody (HBcAb), interferon-α (IFN-α) and interferon-γ (IFN-γ) were measured by enzyme-linked immunosorbent assay (ELISA). The activities of alanine aminotransferase (ALT) were determined by ALT kit using a Spectramax Plus spectrophotometer. Hepatic HBV DNA was quantified by quantitative real-time PCR. The expression of HBV core antigen (HBcAg) in liver was detected by immunohistochemistry. Drug toxicity of CpG-1826 was evaluated by body weighting and liver histopathology confirmation. RESULTS: CpG-1826 administration inhibited HBV replication efficiently with significant reduction of serum HBsAg and HBeAg, hepatic HBcAg and HBV DNA levels. The serum levels of IFN-α, IFN-γ and HBsAb increased but the HBcAb level declined in the CpG-1826 group compared to CpG-1982 and PBS control groups. Results of ALT activity indicated no significant difference among CpG-1826 group, CpG-1982 and PBS control groups. Body weighting and histopathology examination showed no obvious toxicity. CONCLUSIONS: Given the stimulation activity of a host immune system, CpG ODN is a promising strategy for HBV therapy with more relevant research needed.

A simple and efficient strategy for the de novo construction of greater-than-genome-length hepatitis B virus replicons.

Hepatitis B virus (HBV) uses small covalently closed circular DNA for transcription and replication; linearization at any site would destruct at least one HBV open reading frame and interrupt the virus life cycle. Therefore, greater-than-genome-length (GGL) HBV replicons have been widely used for HBV replication studies. However, the existing strategies for the de novo construction of GGL HBV replicons are too complex to implement, especially when multiple replicons need to be cloned. In this study, the pHBV-basic plasmid was constructed for efficient cloning of GGL HBV replicons; changing the orientation of the site for type IIs restriction enzyme SapI in this plasmid reduced the de novo construction of various GGL HBV replicons to only one to three steps. Furthermore, Q5 high-fidelity DNA polymerase was found to be ideal for HBV genome amplification. In vitro experiments showed that the HBV replicon containing 1.31 genome copies replicated with better efficiency as evidenced by the titers of HBV DNA and HBsAg and HBeAg markers. The vector described in this study could serve as a powerful vehicle for in vitro and in vivo investigation of HBV replication.