Spatio-temporal analysis of toxigenic genes expression in the growing Bufo gargarizans based on RNA sequencing data.

BACKGROUND: Bufo gargarizans Cantor, a widely distributed amphibian species in Asia, produces and releases toxins through its retroauricular and granular glands. Although various tissues have been sequenced, the molecular mechanisms underlying the toxin production remain unclear. To elucidate these mechanisms, abdominal skin (non-toxic secretory glands) and retroauricular gland (toxic secreting glands) samples were collected at different time points (3, 6, 12, 24, and 36 months) for RNA sequencing (RNA-seq) and analysis. RESULTS: In comparison to the S group during the same period, a total of 3053, 3026, 1516, 1028, and 2061 differentially expressed genes (DEGs) were identified across five developmental stages. Gene Ontology (GO) analysis revealed that DEGs were primarily enriched in biological processes including cellular processes, single-organism processes, metabolic processes, and biological regulation. In terms of cellular components, the DEGs were predominantly localized in the cell and cell parts, whereas molecular function indicated significant enrichment in binding and catalytic activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the metabolism and synthesis of various substances, such as lipid metabolism, cofactor and vitamin metabolism, tryptophan metabolism, steroid biosynthesis, and primary bile acid biosynthesis, were accompanied by the development of toads. Additionally, using trend analysis, we discovered candidate genes that were upregulated in the retroauricular glands during development, and the abundance of these genes in the abdominal skin was extremely low. Finally, we identified 26 genes that are likely to be involved in toxin production and that are likely to be involved in toxin anabolism. CONCLUSION: Overall, these results provide new insights into the genes involved in toxin production in B. gargarizans, which will improve our understanding of the molecular mechanisms underlying toxigenic gene expression.

Research progress on the structure, derivatives, pharmacological activity, and drug carrier capacity of Chinese yam polysaccharides: A review.

Chinese yam is a traditional Chinese medicine that has a long history of medicinal and edible usage in China and is widely utilised in food, medicine, animal husbandry, and other industries. Chinese yam polysaccharides (CYPs) are among the main active components of Chinese yam. In recent decades, CYPs have received considerable attention because of their remarkable biological activities, such as immunomodulatory, antitumour, hypoglycaemic, hypolipidaemic, antioxidative, anti-inflammatory, and bacteriostatic effects. The structure and chemical alterations of polysaccharides are the main factors affecting their biological activities. CYPs are potential drug carriers owing to their excellent biodegradability and biocompatibility. There is a considerable amount of research on CYPs; however, a systematic summary is lacking. This review summarises the structural characteristics, derivative synthesis, biological activities, and their usage as drug carriers, providing a basis for future research, development, and application of CYPs.

Influence of Engineering Parameters on Fracture Vertical Propagation in Deep Shale Reservoir: A Numerical Study Based on FEM.

The geometry of hydraulic fractures in deep shale facies is significantly affected by the longitudinal inhomogeneity of rock physical properties and stresses. Numerous studies have been conducted on the influence of the longitudinal inhomogeneity of rocks on fracture morphology. However, there is still a lack of research that simultaneously considers the reservoir dip, bedding plane interface, and longitudinal inhomogeneity of the reservoir. To fill this gap, a three-dimensional (3D) numerical model of multireservoir hydraulic fracturing, which takes into account the bedding plane interface, was developed using the finite element method (FEM). The Drucker-Prager elastic-plasticity criterion was incorporated to accurately represent the plasticity of deep shale. The research revealed the influence of the formation dip angle on fracture morphology. Additionally, the perforation layer position and pump rate were optimized based on the actual geological parameters in North Jiangsu shale reservoir. The study findings indicate that reservoir fractures with a formation dip are easily detected by the interface. However, it is not necessarily true that the larger the formation dip, the easier it is for fluids to enter the interface. Fracturing from high-strength and stress reservoirs to lower reservoirs promotes the propagation of fracture height and the connectivity of multiple reservoirs. On the other hand, fractures initiated from low-strength and stress reservoirs tend to be confined to adjacent reservoirs more easily. The pump rate significantly affects the vertical propagation of fractures. At high interface strength, fractures with pump rate below 2.4 m3/min can only propagate at the perforation layer. The limited fracture height in shale reservoirs is likely due to substantial energy consumption by the fracturing fluid at the bedding plane interface. These studies offer theoretical guidance for understanding the vertical propagation of fractures in a deep multilayer reservoir.

Direct-Acting Antivirals Reduce the De Novo Development of Esophageal Varices in Patients with Hepatitis C Virus Related Liver Cirrhosis.

The real-world benefits of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on the de novo occurrence and progression of esophageal varices (EV) remain unclear in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). This is a retrospective cohort study evaluating all patients with Child-Pugh class A HCV-related LC during 2013 to 2020 in the Chang Gung Medical System. A total of 215 patients fit the inclusion criteria and were enrolled. Of them, 132 (61.4%) patients achieved DAA induced-SVR and 83 (38.6%) did not receive anti-viral treatment. During a median follow-up of 18.4 (interquartile range, 10.1−30.9) months, the 2-year incidence of de novo EV occurrence was 8 (7.0%) in the SVR group and 7 (12.7%) in the treatment-naïve group. Compared to the treatment-naïve group, the SVR group was associated with a significantly lower incidence of EV occurrence (adjusted hazard ratio [aHR]: 0.47, p = 0.030) and a significantly lower incidence of EV progression (aHR: 0.55, p = 0.033). The risk of EV progression was strongly correlated with the presence of baseline EV (p < 0.001). To the best of our knowledge, this is the first study to demonstrate that DAA-induced SVR is associated with decreased risk of de novo EV occurrence and progression in the real world.

A novel polysaccharide from Lonicerae Japonicae Caulis: Characterization and effects on the function of fibroblast-like synoviocytes.

A novel polysaccharide (LJCP-2b) was isolated from Lonicerae Japonicae Caulis, and its structural features were identified by molecular weight distribution, infrared spectrum, monosaccharide composition, methylation analysis and NMR. LJCP-2b was a homogeneous heteropolysaccharide with a molecular weight of 7.0 kDa and composed of glucose, galacturonic acid, galactose, arabinose, rhamnose, xylose, mannose and glucuronic acid. Structural analysis revealed that LJCP-2b was mainly consisted of 1,3,6-ß-D-Galp, 1,4-α-D-Glcp, 1,4,6-α-D-Glcp, 1,4-ß-D-Galp, 1,2,4-α-L-Rhap and 1,4-α-D-GalpA. In vitro experiments showed that LJCP-2b could affect the function of TNF-α-induced rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), including weakening cell viability, increasing apoptosis rate, decreased migration number and adhesion capacity, and reduced the levels of IL-6 and IL-1ß. These results indicated that LJCP-2b exhibited the activity of inhibiting the hyperproliferation and inflammatory response of RA-FLS, which may be developed for prevention or treatment of RA.

Hepatitis C-associated late-onset schizophrenia: a nationwide, population-based cohort study.

BACKGROUND: Whether infection with the hepatitis C virus (HCV) causes schizophrenia - and whether the associated risk reverses after anti-HCV therapy - is unknown; we aimed to investigate these topics. METHODS: We conducted a nationwide, population-based cohort study using the Taiwan National Health Insurance Research Database (TNHIRD). A diagnosis of schizophrenia was based on criteria from the International Classification of Diseases, 9th revision (295.xx). RESULTS: From 2003 to 2012, from a total population of 19 298 735, we enrolled 3 propensity-score-matched cohorts (1:2:2): HCV-treated (8931 HCV-infected patients who had received interferon-based therapy for ≥ 6 months); HCV-untreated (17 862); and HCV-uninfected (17 862) from the TNHIRD. Of the total sample (44 655), 82.81% (36 980) were 40 years of age or older. Of the 3 cohorts, the HCV-untreated group had the highest 9-year cumulative incidence of schizophrenia (0.870%, 95% confidence interval [CI] 0.556%-1.311%; p < 0.001); the HCV-treated (0.251%, 95% CI 0.091%-0.599%) and HCV-uninfected (0.118%, 95% CI 0.062%-0.213%) cohorts showed similar cumulative incidence of schizophrenia (p = 0.33). Multivariate Cox analyses showed that HCV positivity (hazard ratio [HR] 3.469, 95% CI 2.168-5.551) was independently associated with the development of schizophrenia. The HCV-untreated cohort also had the highest cumulative incidence of overall mortality (20.799%, 95% CI 18.739%-22.936%; p < 0.001); the HCV-treated (12.518%, 95% CI 8.707%-17.052%) and HCV uninfected (6.707%, 95% CI 5.533%-8.026%) cohorts showed similar cumulative incidence of mortality (p = 0.12). LIMITATIONS: We were unable to determine the precise mechanism of the increased risk of schizophrenia in patients with HCV infection. CONCLUSION: In a population-based cohort (most aged ≥ 40 years), HCV positivity was a potential risk factor for the development of schizophrenia; the HCV-associated risk of schizophrenia might be reversed by interferon-based antiviral therapy.

Critical role of triglycerides for adiponectin levels in hepatitis C: a joint study of human and HCV core transgenic mice.

BACKGROUND: Both hepatitis C virus (HCV) infection and adiponectin are critically involved in metabolism. The reversal and associations of altering adiponectin levels after sustained virological responses (SVRs) following direct-acting antivirals (DAA) in HCV-infected patients remained elusive. METHODS: A joint study was conducted in a prospective cohort of 427 HCV-infected patients and a line of HCV core transgenic mice. RESULTS: Of 427, 358 had completed a course of DAA therapy and 353 had SVRs. At baseline, male sex (95% CI ß: - 1.44 to - 0.417), estimated glomerular filtration rate (eGFR) (- 0.025 to - 0.008), triglycerides (- 0.015 to - 0.005), and fibrosis-4 levels (0.08-0.297) were associated with adiponectin levels; BMI (0.029-0.327) and triglycerides levels (0.01-0.03) were associated with homeostatic model assessment for insulin resistance (HOMA-IR) in HCV-infected patients. At 24-week post-therapy, in SVR patients, male sex (- 1.89 to - 0.5) and eGFR (- 0.02 to - 0.001) levels were associated with adiponectin levels, levels of BMI (0.094-0.335) and alanine transaminase (0.018-0.078) were associated with HOMA-IR; compared with baseline levels, adiponectin levels decreased (6.53 ± 2.77 vs. 5.45 ± 2.56 µg/mL, p < 0.001). In 12-month-old HCV core transgenic mice with hepatic steatosis, triglyceride levels (0.021-0.111) were associated with adiponectin levels, and hepatic adipopnectin expression was comparable with that of control mice. CONCLUSIONS: Triglycerides and hepatic fibrosis are associated with HCV-specific alteration of adiponectin levels, and adiponectin may affect insulin sensitivity through triglycerides during HCV infection. In DAA-treated patients, after SVR, adiponectin levels decreased and the linking function of triglycerides between adiponectin and insulin sensitivity vanished. Moreover, HCV core with hepatic steatosis might affect extrahepatic adiponectin expression through triglycerides.

Identification of the Representative Primary Biliary Cholangitis Cohort in Taiwan: A Comparison of Four Nationwide Cohorts.

BACKGROUND/PURPOSE: The rates and outcomes of primary biliary cholangitis (PBC) in Taiwan remain unclear. METHODS: A nationwide population-based cohort study (Taiwan National Health Insurance Research Database, 2002-2015) was conducted. Data from four PBC cohorts with various definitions were compared (cohort 1 (C1): ICD-9-CM (571.6); C2: alkaline phosphatase (Alk-P) and antimitochondrial antibody (AMA) measurements; C3: Alk-p and AMA measurements and ursodeoxycholic acid (UDCA) treatment; C4: ICD-9-CM (571.6), Alk-p and AMA measurements and UDCA treatment). RESULTS: The average prevalence rate ranged from 9.419/105 (C4) to 307.658/105 (C2), and the female-to-male ratio ranged from 1.192 (C1) to 3.66 (C4). Prevalence rates increased over time in all cohorts. The average incidence rates ranged from 1.456/105 (C4) to 66.386/105 (C2). Incidence rates decreased over time in C1 (-9.09%, p < 0.0001) and C4 (-6.68%, p < 0.0001) and remained steady in the others. C4 had the lowest prevalence and incidence rates and highest female-to-male ratio. Cirrhosis rates ranged from 7.21% (C2) to 39.34% (C4), hepatoma rates ranged from 2.77%(C2) to 6.66%(C1), liver transplantation (LT) rates ranged from 1.07% (C2) to 6.77% (C4), and mortality rates ranged from 18.24% (C2) to 47.36% (C1). C4 had the highest LT (6.77%), osteoporosis (13.87%) and dyslipidemia rates (17.21%). CONCLUSIONS: Based on the reported ranges of reasonable rates, female predominance and characteristic outcomes, C4 was the most representative Taiwanese PBC cohort, with average prevalence and incidence rates of 9.419/105 and 1.456/105, respectively, and a female-to-male ratio of 3.66. In a 14-year period, cirrhosis, hepatoma, LT, and mortality were noted in 39.34%, 5.52%, 6.77%, and 34.22% of C4 patients, respectively.

Inhibition of dynamin-related protein 1 ameliorates the mitochondrial ultrastructure via PINK1 and Parkin in the mice model of Parkinson's disease.

Parkinson's disease (PD) is the prevalent neurodegenerative disorder characterized by the degeneration of the nigrostriatal neurons. Dynamin-related protein 1 (Drp1) is a key regulator mediating mitochondrial fission and affecting mitophagy in neurons. It has been reported that the inhibition of Drp1 may be beneficial to PD. However, the role of Drp1 and mitophagy in PD remains elusive. Therefore, in this research, we investigated the role of Drp1 and the underlying mechanisms in the mice model of PD. We used the dynasore, a GTPase inhibitor, to inhibit the expression of Drp1. We found that inhibition of Drp1 could ameliorate the motor deficits and the expression of tyrosine hydroxylase in the mice of the PD model. But Drp1 inhibition did not affect mitochondria number and morphological parameters. Moreover, suppression of Drp1 up-regulated the mitochondrial expressions of PINK1 and Parkin while not affected the expressions of NIX and BNIP3. Conclusively, our findings suggest that the inhibition of Drp1 ameliorated the mitochondrial ultrastructure at least via regulating PINK1 and Parkin in the mice of the PD model. This study also implicates that inhibition of Drp1 might impact mitophagy and recover mitochondrial homeostasis in PD.

Toad venom: A comprehensive review of chemical constituents, anticancer activities, and mechanisms.

Toad venom, a traditional natural medicine, has been used for hundreds of years in China for treating different diseases. Many studies have been performed to elucidate the cardiotonic and analgesic activities of toad venom. Until the last decade, an increasing number of studies have documented that toad venom is a source of lead compound(s) for the development of potential cancer treatment drugs. Research has shown that toad venom contains 96 types of bufadienolide monomers and 23 types of indole alkaloids, such as bufalin, cinobufagin, arenobufagin, and resibufogenin, which exhibit a wide range of anticancer activities in vitro and, in particular, in vivo for a range of cancers. The main antitumor mechanisms are likely to be apoptosis or/and autophagy induction, cell cycle arrest, cell metastasis suppression, reversal of drug resistance, or growth inhibition of cancer cells. This review summarizes the chemical constituents of toad venom, analyzing their anticancer activities and molecular mechanisms for cancer treatments. We also outline the importance of further studies regarding the material basis and anticancer mechanisms of toad venom.

Impact of Interferon-Based Therapy on Hepatitis C-Associated Rheumatic Diseases: A Nationwide Population-Based Cohort Study.

Whether hepatitis C virus (HCV) infection-associated risk of rheumatic diseases is reversed by anti-HCV therapy remain elusive. A nationwide population-based cohort study of the Taiwan National Health Insurance Research Database was conducted. Of 19,298,735 subjects, 3 cohorts (1:4:4, propensity score-matched), including HCV-treated (6919 HCV-infected subjects with interferon and ribavirin therapy ≥ 6 months), HCV-untreated (n = 27,676) and HCV-uninfected (n = 27,676) cohorts, were enrolled and followed (2003-2015). The HCV-uninfected cohort had the lowest cumulative incidence of rheumatic diseases (95% confidence interval (CI): 8.416-10.734%), while HCV-treated (12.417-17.704%) and HCV-untreated (13.585-16.479%) cohorts showed no difference in the cumulative incidences. Multivariate analyses showed that HCV infection (95% CI hazard ratio (HR): 1.54-1.765), female sex (1.57-1.789), age ≥ 49 years (1.091-1.257), Charlson comorbidity index ≥ 1 (1.075-1.245), liver cirrhosis (0.655-0.916), chronic obstruction pulmonary disease (1.130-1.360), end-stage renal disease (0.553-0.98), diabetes mellitus (0.834-0.991) and dyslipidemia (1.102-1.304) were associated with incident rheumatic diseases. Among the 3 cohorts, the untreated cohort had the highest cumulative incidence of overall mortality, while the treated and un-infected cohorts had indifferent mortalities. Conclusions: HCV infection, baseline demographics and comorbidities were associated with rheumatic diseases. Although HCV-associated risk of rheumatic diseases might not be reversed by interferon-based therapy, which reduced the overall mortality in HCV-infected patients.

Usefulness of quantitative hepatitis B surface antigen testing in hepatitis B community-based screening.

BACKGROUND/PURPOSE: Low viral load (LVL) of hepatitis B virus (HBV) is a predictor of chronic HBV infection. However, the usefulness of quantitative hepatitis B surface antigen (qHBsAg) in predicting LVL in community-based screening has not been well studied. We aimed to measure the prevalence of LVL in HBV carriers and validate the efficacy of qHBsAg in predicting LVL. METHODS: This community-based screening study was conducted in Taiwan. HBV DNA was assayed in HBsAg carriers. Participants were randomized to training and validation sets to determine the ability of qHBsAg to predict LVL. Receiver operating characteristic curves were used to identify the best cutoff values in the training set. RESULTS: Among the 2919 participants, 359 (12.2%) were HBsAg carriers. There were 132 and 137 carriers in the training and validation sets, respectively. Significant correlations were found between qHBsAg and HBV DNA in both training and validation sets. Thirty and 29 participants with qHBsAg <8 IU/mL in the training and validation sets, respectively, had LVL. Using 8 IU/mL as the cutoff, negative predictive value (NPV) of qHBsAg for HBV DNA levels >2000 IU/mL was 100%. The best cutoff level of qHBsAg to predict HBV LVL was 200 IU/mL, with a sensitivity, specificity, and accuracy of 75.0%, 76.1%, and 75.8%, respectively, in the training set. The positive predictive value and NPV were 70.0% and 77.9%, respectively, in the validation set. CONCLUSION: Approximately 60% of HBsAg carriers had HBV LVL, and qHBsAg <8 IU/mL accurately predicts LVL. This quantitative test provides additional information for community-based screening.

Naringenin ameliorates homocysteine induced endothelial damage via the AMPKα/Sirt1 pathway.

Introduction: Endothelial damage (ED) has been implicated in accelerating the development of atherosclerosis. The latter condition is a risk factor for developing several cardiovascular diseases (CVDs) associated with high morbidity and mortality rates worldwide. Objectives: In our previous studies, we found naringenin (Nar), a bioactive flavanone compound, to protect against mitochondrial damage and oxidative stress. Though the pleiotropic effects of Nar have been well described, precise cytoprotective mechanisms of Nar against homocysteine (Hcy) induced ED remains elusive. Understanding these events may give an insight in to prevention and treatment of CVDs. Methods: After ruling out the NMDA-R1 mediated pathway, RNA-Seq, a novel transcriptomic technique uncovered AMPK signaling pathway was identified as the mechanism with which Nar corrects ED. Further in vivo and in vitro tests validated the role of Nar against ED. Results: In particular, Nar activates AMPKα/Sirt1 signaling pathway, which restores mitochondrial Ca2+ balance and ultimately lowered production of reactive oxygen species (ROS). Activated AMPKα/Sirt1 signaling pathway also up-regulates endothelial nitric oxide synthase (eNOS) activity, and then increasing the production of nitric oxide (NO), ultimately ameliorating ED. Conclusion: Nar could increase the ROS elimination and decrease eNOS uncoupling, subsequently upregulate the NO bioavailability and endothelial function by activating AMPKα/Sirt1 signaling pathway.

Interactive Impacts from Hepatitis C Virus Infection and Mixed Cryoglobulinemia on Complement Levels.

BACKGROUND/AIM: How hepatitis C virus (HCV) infection and mixed cryoglobulinemia interactively affect complement levels remains elusive, and we aimed to elucidate it. METHODS: A prospective cohort study of 678 consecutive chronic HCV-infected (CHC) patients was conducted. Of 678, 438 had completed a course of anti-HCV therapy and 362 had achieved a sustained virological response (SVR). The baseline and 24-week post-therapy variables including complement levels and mixed cryoglobulinemia status were surveyed. RESULTS: At baseline, lower complement component 3 (C3) and component 4 (C4) levels were noted in patients with than those without mixed cryoglobulinemia. The differences between pre-therapy (in 678 CHC patients) and 24-week post-therapy (in 362 SVR patients) factors associated with C3 levels were interferon λ3 (IFNL3) genotype, triglycerides, cirrhosis, and estimated glomerular filtration rate; the different associations with C4 levels were cirrhosis, sex and high sensitivity C-reactive protein. Compared with baseline, SVR patients without pre- and post-therapy mixed cryoglobulinemia had increased C3 levels, and SVR patients with pre-therapy mixed cryoglobulinemia had increased C4 levels. Lower C3 levels were noted in SVR patients with than those without post-therapy mixed cryoglobulinemia. CONCLUSIONS: HCV might affect C3 levels through IFNL3 genotype, triglycerides, cirrhosis, and renal function; and affect C4 with a link to sex, inflammation, and cirrhosis. That C3 levels decreased in CHC patients without mixed cryoglobulinemia or in SVR patients with post-therapy mixed cryoglobulinemia, and C4 levels decreased in CHC patients with mixed cryoglobulinemia, suggested that mixed cryoglobulinemia and HCV infection antagonistically and synergistically decrease C3 and C4 levels, respectively.

Altering retinol binding protein 4 levels in hepatitis C: Inflammation and steatosis matter.

Both hepatitis C virus (HCV) infection and retinol-binding protein 4 (RBP4) might contribute to insulin resistance (IR), how RBP4 links to IR in HCV infection remain elusive. A joint study of a prospective cohort of 842 chronically HCV-infected (CHC) patients (with 842 controls) and a line of HCV core transgenic mice was conducted. Of 842 patients, 771 had completed anti-HCV therapy and 667 had sustained virological responses (SVRs). Compared with controls, CHC patients had lower RBP4 levels. At baseline, age (95% CI ß: -0.87~-0.317), BMI (0.516~2.036), triglycerides (0.03~0.127), neutrophil-to-lymphocyte ratio (NLR) (1.561~7.327), and estimated glomerular filtration rate (eGFR) (-0.342~-0.149) levels were associated with RBP4 levels in CHC patients. At 24-week post-therapy, male sex (0.652~8.129), BMI (0.199~1.254), triglycerides (0.039~0.088), uric acid (0.599~3.067), eGFR (-0.247 ~-0.14) levels, and fibrosis-4 (-3.602~-0.039) scores were associated with RBP4 levels in SVR patients; compared with baseline, except genotype 3 HCV-infected patients, SVR patients had increased RBP4 levels, which were comparable with controls, while no HOMA-IR index alteration was noted after SVR. The HCV core transgenic mice exhibited nonobese hepatic steatosis, had higher hepatic RBP4 expression, higher serum levels of RBP4 and triglycerides, but comparable HOMA-IR levels than non-transgenic littermates. In conclusion, steatosis, sex, age, uric acid, NLR, and FIB-4 levels were associated with HCV-related RBP4 levels; BMI, triglycerides, and eGFR levels were associated with non-HCV-related RBP4 levels. Reversal of low RBP4 levels after SVR was evident in non-genotype 3 HCV-infected patients. Steatosis and inflammation linked with metabolic alteration other than IR, determined RBP4 levels in HCV-infected patients.

Evolution of ferritin levels in hepatitis C patients treated with antivirals.

The evolution of ferritin levels in hepatitis C virus (HCV)-infected patients with sustained virological responses (SVRs) following various therapy regimens remains elusive. An 8-year prospective cohort study of 1194 HCV-infected patients [interferon-based therapy (n = 620), direct-acting antiviral agent (DAA) therapy (n = 355)] was conducted. At baseline, sex, alanine aminotransferase (ALT), triglycerides, homeostatic model assessment of insulin resistance (HOMA-IR), estimated glomerular filtration rate (eGFR), hemoglobin, iron/total iron-binding capacity (Fe/TIBC) and IFNL3-rs12979860 genotypes were associated with ferritin levels. At 24 weeks posttherapy, ALT, triglycerides, total cholesterol, eGFR, Fe/TIBC and the therapy regimen were associated with ferritin levels in SVR patients. Among interferon-treated patients, ferritin levels increased at 24 weeks posttherapy, regardless of SVR, and 24-week posttherapy ferritin levels were higher in non-SVR patients (n = 111) than in SVR patients (n = 509); ferritin levels began decreasing at 3 years posttherapy and were lower than pretherapy levels since 4 years posttherapy in SVR patients. Among DAA-treated SVR patients (n = 350), ferritin levels decreased and remained stable since 24 weeks posttherapy. ALT, triglycerides, eGFR, and Fe/TIBC were HCV-unrelated factors associated with ferritin levels; sex, HOMA-IR, total cholesterol, hemoglobin and IFNL3-rs12979860 genotype were HCV-related factors associated with ferritin levels. In interferon-treated SVR patients, the increased trend of posttherapy ferritin levels was not reversed until 4 years posttherapy. In DAA-treated SVR patients, ferritin levels decreased since 24 weeks posttherapy.

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers.

Multidrug resistance (MDR) is the dominant challenge in the failure of chemotherapy in cancers. Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that spreads intracellular signal cascades and regulates a variety of cellular processes. PI3Ks are considered significant causes of chemoresistance in cancer therapy. Protein kinase B (AKT) is also a significant downstream effecter of PI3K signaling, and it modulates several pathways, including inhibition of apoptosis, stimulation of cell growth, and modulation of cellular metabolism. This review highlights the aberrant activation of PI3K/AKT as a key link that modulates MDR. We summarize the regulation of numerous major targets correlated with the PI3K/AKT pathway, which is further related to MDR, including the expression of apoptosis-related protein, ABC transport and glycogen synthase kinase-3 beta (GSK-3ß), synergism with nuclear factor kappa beta (NF-κB) and mammalian target of rapamycin (mTOR), and the regulation of glycolysis.

Purification and characterization of a novel fibrinolytic enzyme from Whitmania pigra Whitman.

Developing an effective fibrinolytic drug for treating thrombolysis with minimal undesirable side effects is of great importance. In the current study, an optimum solvent was selected for the extraction of fibrinolytic active components. Furthermore, a strong fibrinolytic enzyme named WPI01 was purified from Whitmania pigra Whitman through various chromatographic steps. WPI01 has a molecular mass of 27044.297 Da, and the N-terminal 8 amino acid sequence was determined as VVGGVEAR. WPI01 was stable within the pH range of 6.0-10.0 and with maximum fibrinolytic activity at 40 °C and a pH of 8.0. At 500 U/mL, WPI01 induced 50.59% blood clot reduction in vitro within 6 h, which was higher than that induced by urokinase at 1000 U/mL. In an analysis of the plasminogen activator activity, WPI01 produced obvious halos on heated and unheated fibrin plates, suggesting that WPI01 may not only act as a plasminogen activator but also degrade fibrin clots directly, and more study is needed to support this. In conclusion, WPI01 is obviously different from known fibrinolytic enzymes in terms of substrate specificity and fibrinolytic mode of action, suggesting that it is a novel fibrinolytic enzyme with potential applications in the treatment and prevention of thrombosis.

Erratum: Effect of HCV treatment response on insulin resistance: A systematic review and meta-analysis.

[This corrects the article DOI: 10.3892/etm.2019.7995.].

Effect of HCV treatment response on insulin resistance: A systematic review and meta-analysis.

Sustained virological response (SVR) in hepatitis C virus (HCV) patients treated with pegylated interferon α-2a and ribavirin is associated with reduced insulin resistance (IR), measured as a reduction of homeostasis model assessment (HOMA) scores after 24 weeks of therapy, and reduced fasting serum insulin and serum glucose levels. The present meta-analysis aimed to evaluate the effect of HCV treatment response on IR in HCV patients who achieved SVR and those who did not (non-SVR) after receiving interferon (IFN)-based therapy. The PubMed, Cochrane and Embase databases were searched using combinations of the following search terms: 'HCV', 'hepatitis C', 'interferon', 'antiviral', 'treatment response' and 'insulin resistance'. The incidence of IR, HOMA-IR and HOMA-ß, as well as fasting glucose and fasting insulin levels, were summarized in terms of basal values and values after the end of treatment for each study. A total of 8 studies were included in the final analysis. There was no significant difference in the reduction in IR between the SVR and non-SVR groups (odds ratio, 0.995; 95% CI=0.613-1.616; P=0.984). However, the SVR group had a significantly higher mean reduction in HOMA-IR (difference in means=-0.485; 95%CI=-0.713 to -0.256; P<0.001) and HOMA-ß (difference in means=-15.448; 95%CI=-23.326 to -7.570; P<0.001) compared to the non-SVR group. In conclusion, HCV patients who achieved SVR after IFN-based therapy exhibited improvement in HOMA-IR and HOMA-ß. The present results suggest that clinical management of IR and serum glucose levels may be an important way to impact the therapeutic response in HCV patients.