Synthesis and antitumor activities of novel 3-(6-aminopyridin-3-yl)benzamide derivatives: Inducing cell cycle arrest and apoptosis via AURKB transcription inhibition.

Here, a series of 3-(6-aminopyridin-3-yl) benzamide derivatives were designed and synthesized. Cell viability assay indicated that most compounds exhibited potent antiproliferative activity against all the tested cancer cells. Among them, compound 7l displayed the best antiproliferative activity particularly in A549 cells, with an IC50 value of 0.04 ± 0.01 µM. RNA-seq analysis was employed to explore the potential pathways related to the antiproliferative activity of compound 7l. The data revealed that 7l exerted antiproliferative activity mainly by regulating cell cycle, DNA replication and p53 signaling pathway. Indeed, compound 7l induced G2/M phase arrest by AURKB transcription inhibition and resulted in cell apoptosis via p53 signaling pathway. Most importantly, compound 7l demonstrated potent antitumor activity in A549 xenograft tumor model. Collectively, 7l might be a promising lead compound for the development of new therapeutic agents for AURKB overexpressed or mutated cancers.

Corrigendum: Cuproptosis key gene FDX1 is a prognostic biomarker and associated with immune infiltration in glioma.

[This corrects the article DOI: 10.3389/fmed.2022.939776.].

The effectiveness of combination therapy with interferon and nucleoside analogs in pediatric patients with chronic hepatitis B: a systematic review and meta-analysis.

BACKGROUND: It is a challenging issue regarding the optimal antiviral treatment of children with chronic hepatitis B (CHB). The efficacy comparison of interferon (IFN) or nucleos(t)ide analogs (NAs) monotherapy with their combination could better understand this issue. METHODS: PubMed, EMBASE, Cochrane Library, Wanfang, CNKI, and abstracts of major international hepatology meetings were searched from inception to Feb 8, 2022. Randomized control trials and observational studies reporting the efficacy of combination therapy with IFN and NAs in children with CHB were eligible. RESULTS: A total of 17 studies were included. Compared with IFN monotherapy, combination therapy with IFN and NAs was significantly associated with increased rates of HBV DNA undetectable, HBeAg clearance, HBeAg seroconversion, alanine transaminase (ALT) normalization as well as the composite treatment response both at the end of treatment and during the follow-up period (RRs ranged from 1.23 to 1.75). A favorable trend for HBsAg seroconversion was found in IFN plus NAs-treated children, but not for the HBsAg clearance at the end of treatment. Although a similar trend towards the superiority of the combination therapy versus NAs monotherapy was observed (RRs ranged from 1.24 to 2.33) except for the HBV DNA undetectable rate at the end of treatment, the number of reported studies was limited. CONCLUSIONS: Combination therapy with IFN and NAs is more effective than IFN monotherapy in viral suppression and serological response for children with CHB. More studies were still needed to reveal the efficacy of this combination therapy compared with NAs monotherapy.

Cuproptosis key gene FDX1 is a prognostic biomarker and associated with immune infiltration in glioma.

Recent studies have found that the protein encoded by the FDX1 gene is involved in mediating Cuproptosis as a regulator of protein lipoylation and related to immune response process of tumors. However, the specific biological function of FDX1 in glioma is currently unclear. To explore the potential function of FDX1, this study explored the correlation between the expression of FDX1 in cancers and survival prognosis by analyzing the public databases of GEPIA and Cbioportal. Immune infiltration was analyzed by the TIMER2.0 database in tumors. The possible biological processes and functions of FDX1-related in glioma were annotated through gene enrichment. Relationship between Cuproptosis and autophagy was explored through gene co-expression studies. Summary and conclusions of this study: (1) FDX1 is highly expressed in gliomas and associated with poor prognosis in low-grade gliomas (LGG). (2) Gene annotation indicates that FDX1 is mainly involved in the tumor protein lipoylation and cell death. (3) FDX1 expression is positively correlated with the infiltration of immune cells. (4) LIPT2 and NNAT, two other genes involved in lipoylation, may be unidentified marker gene for Cuproptosis. And the Cuproptosis genes related to FDX1 were positively correlated with the expression of autophagy marker genes Atg5, Atg12, and BECN-1. This evidence suggests that there may be some interaction between FDX1 mediated Cuproptosis and autophagy. In summary, FDX1 may serve as a potential immunotherapy target and prognostic marker for Glioma.

Increased Risk of Ocular Hypertension in Patients With Cushing's Disease.

PRCIS: An increased risk of ocular hypertension was seen in Cushing's disease. INTRODUCTION: Systemic steroid use is a significant risk factor for increased intraocular pressure (IOP). The incidence of ocular hypertension may rise to 30%-40% of the general population due to topical or systemic glucocorticoid usage. However, the incidence of ocular hypertension in endogenous hypercortisolemia, as well as the ophthalmological outcomes after endocrine remission due to surgical resection, remain unknown. MATERIALS AND METHODS: The IOP, visual field, and peripapillary retinal nerve fiber layer thickness were documented in all patients with Cushing's disease (CD) admitted to a tertiary pituitary center for surgery from January to July 2019. Patients with acromegaly and patients with nonfunctioning pituitary adenoma (NFPA) during the same study period served as controls. We calculated the odds ratio (OR), identified the risk factors of developing ocular hypertension, and presented postoperative trends of the IOP. RESULTS: A total of 52 patients (38.4±12.4 y old) with CD were included. The IOP was higher in patients with CD (left 19.4±5.4 mm Hg and right 20.0±7.1 mm Hg) than in patients with acromegaly (left 17.5±2.3 mm Hg and right 18.6±7.0 mm Hg, P =0.033) and patients with NFPA (left 17.8±2.6 mm Hg and right 17.4±2.4 mm Hg, P =0.005). A total of 21 eyes (20.2%) in patients with CD were diagnosed with ocular hypertension compared with 4 eyes (4.7%) in the acromegaly group and 4 eyes (4.5%) in the NFPA group. The OR of developing ocular hypertension in patients with CD was 5.1 [95% confidence interval (CI), 1.3-25.1, P =0.029] and 6.6 (95% CI, 1.8-30.3, P =0.007) when compared with the 2 control groups. Among patients with CD, those with a higher urine-free cortisol were more likely to develop ocular hypertension (OR=19.4, 95% CI, 1.7-72.6). The IOP decreased at 1 month after surgery in patients with CD, and the change was sustained for 3 months after surgery. CONCLUSIONS: An increased risk of ocular hypertension was seen in CD and suggests that endogenous hypercortisolemia should be considered as part of the glaucoma assessment. This result warrants the discretion of both ophthalmologists and neuroendocrinologists.

Sources and symptoms of stress among nurses in the first Chinese anti-Ebola medical team during the Sierra Leone aid mission: A qualitative study.

OBJECTIVE: This study investigated the sources of stress, corresponding symptoms, and stress relief among nurses of the first Chinese anti-Ebola medical team during the Sierra Leone aid mission. METHOD: A purposive sampling method was used and 10 nurses were selected from the first Chinese anti-Ebola medical team that was dispatched to Sierra Leone. Data were collected via phone and semi-structured interviews, then analyzed using Colaizzi's seven-step method. RESULTS: The data showed three major themes: (1) The causes of stress during the Sierra Leone aid mission mainly related to unsafety, responsibility, and unfamiliarity; (2) Physical, cognitive, emotional, and behavioral symptoms were documented; (3) Nurses experienced relief from stress after the mission. CONCLUSION: Targeted measures, proper responses and good community support can effectively lower stress among nurses on anti-Ebola missions.

San-Cao Granule () Ameliorates Hepatic Fibrosis through High Mobility Group Box-1 Protein/Smad Signaling Pathway.

OBJECTIVE: To investigate the possible mechanism of San-Cao Granule (SCG, ) mediating antiliver fibrosis. METHODS: A total of 60 male Sprague-Dawley rats were randomly divided into the normal control group, porcine serum-treated group, ursodesoxycholic acid (UDCA, 60 mg/kg), SCG (3.6 g/kg) group, SCG (1.8 g/kg) group and SCG (0.9 g/kg) group, with 10 rats in each group. Liver fibrosis was induced with porcine serum by intraperitoneal injection for 8 weeks, except for the normal control group. Then, the rats in the three SCG-treated groups and UDCA group were administered SCG and UDCA respectively for 4 weeks. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), albumin (ALB), total bilirubin (TBIL), hyaluronic acid (HA), laminin (LN), and type IV collagen (IVC) were examined using commercial kits and hepatic histopathology was examined with hematoxylin and eosin and Masson staining. Moreover, the protein expression levels of high mobility group box-1 protein (HMGB1), transforming growth factor ß1 (TGF-ß1), phosphorylated mothers against decapentaplegic homolog 3 (p-Smad3), Smad7, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor-kappa B (NF-κB) and α-smooth muscle actin (α-SMA) were determined by western blot, immunohistochemistry and real time quantitative-reverse transcription polymerase. RESULTS: Both SCG (3.6 and 1.8 g/kg) and UDCA significantly ameliorated the liver fibrosis induced by porcine serum as indicated by retarding the serum levels increasing of ALT, AST, TBIL, HA, LN and IVC and preventing the serum level reducing of ALB compared with the model group (all P<0.01). Meanwhile, the collagen deposition was attenuated by SCG and UDCA treatment. Furthermore, SCG markedly reduced the expressions of HMGB1, TGF-ß1, p-Smad3, TLR4, MyD88, NF-κB and α-SMA, and enhanced the expression of the Smad7 compared with the model group (all P<0.01). CONCLUSION: SCG ameliorates hepatic fibrosis possibly through inhibiting HMGB1, TLR4/NF-κB and TGF-ß1/Smad signaling pathway.

Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces.

UNLABELLED: Chronic passive hepatic congestion (congestive hepatopathy) leads to hepatic fibrosis; however, the mechanisms involved in this process are not well understood. We developed a murine experimental model of congestive hepatopathy through partial ligation of the inferior vena cava (pIVCL). C57BL/6 and transgenic mice overexpressing tissue factor pathway inhibitor (SM22α-TFPI) were subjected to pIVCL or sham. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, real-time polymerase chain reaction, and western blot assays. Hepatic fibrosis and portal pressure were significantly increased after pIVCL concurrent with hepatic stellate cell (HSC) activation. Liver stiffness, as assessed by magnetic resonance elastography, correlated with portal pressure and preceded fibrosis in our model. Hepatic sinusoidal thrombosis as evidenced by fibrin deposition was demonstrated both in mice after pIVCL as well as in humans with congestive hepatopathy. Warfarin treatment and TFPI overexpression both had a protective effect on fibrosis development and HSC activation after pIVCL. In vitro studies show that congestion stimulates HSC fibronectin (FN) fibril assembly through direct effects of thrombi as well as by virtue of mechanical strain. Pretreatment with either Mab13 or Cytochalasin-D, to inhibit ß-integrin or actin polymerization, respectively, significantly reduced fibrin and stretch-induced FN fibril assembly. CONCLUSION: Chronic hepatic congestion leads to sinusoidal thrombosis and strain, which in turn promote hepatic fibrosis. These studies mechanistically link congestive hepatopathy to hepatic fibrosis.

Combining Oxymatrine or Matrine with Lamivudine Increased Its Antireplication Effect against the Hepatitis B Virus In Vitro.

Some recent clinical reports have shown that the combination of oxymatrine, a phyto-derived drug, with lamivudine (3TC) could improve its curative effect against hepatitis B virus (HBV) infection. However, the experimental data in support of this combination strategy are lacking. In this study, we investigated the anti-HBV activity of the combination of 3TC and either oxymatrine or matrine on HepG2 2.2.15 in vitro. The activities of the combination and the solo compound, each in different concentrations, were compared on the 3rd, 6th, and 9th experimental days. The cytotoxicity results showed that the nontoxic concentrations of both oxymatrine and matrine to HepG2 2.2.15 cells were 800 µg/mL. We found that the single use of oxymatrine below 100 µg/ml, matrine below 200 µg/ml, and 3TC below 30 µg/ml showed weak inhibitory effects on the secretion of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV-DNA in culture media; the combination of 3TC (30 µg/ml) with oxymatrine (100 µg/ml) or matrine (100 µg/ml) showed significant inhibitory effects that were higher than or equivalent to the single use of 3TC at 100 µg/ml. The results provide a new impetus to develop novel, multicomponent anti-HBV drugs through the combination of natural products with nucleoside analogs to enhance their activity.

Sensitivity of a label-free guided-mode resonant optical biosensor with different modes.

Sensitivity is a key factor in the performance of a sensor. To achieve maximum guided-mode resonant optical biosensor sensitivity, a comparison of biosensor sensitivity for Transverse Electric (TE) and Transverse Magnetic (TM) modes based on the distribution of electric fields is presented in this article. A label-free guided-mode resonant optical biosensor is designed using the quarter-wave anti-reflection method to reflect only a narrow band of wavelengths modulated by the adsorption of a biochemical material on the sensor surface at the reflected frequency. With the distribution of electric fields simulated according to the Rigorous Coupled Wave Analysis (RCWA) theory, it is found that the full width at half maximum of the TM mode is (≈ 4 nm) narrower than that of the TE mode (≈ 20 nm), and the surface sensitivity of the TE mode incident light is three times that of the TM mode. It is proposed in this article that the light mode plays an important role in the sensitivity of guided-mode resonant biosensors.

The diarrhoeogenic and antidiarrhoeal bidirectional effects of rhubarb and its potential mechanism.

AIM OF THE STUDY: The present study investigated the pharmacological effects of different extracts of rhubarb on intestinal function of mice, further to explore possible reasons for the adverse effects of long-term use of rhubarb as a purgative. MATERIALS AND METHODS: The total extract of rhubarb (TR) was extracted with 60% ethanol and the total anthraquinones extract (TA), total tannins extract (TT) and remaining components extract (RC) of rhubarb were separated from TR using macroporous resin. The pharmacological effects of each extract on the intestinal function of mice were evaluated by defecation test and the antidiarrhoeal activity of rhubarb tannins as well as its mechanism was studied by different animal models and histopathological examination. RESULTS: Both TR and TA produced purgative activities, but the purgative activity of TA was stronger than that of TR. Successive administration of TT produced an antidiarrhoeal activity in a time- and dose-dependent manner. Besides, successive administration of RC showed no significant effect on the intestinal function of mice. The antidiarrhoeal activity of rhubarb tannins was confirmed directly for the first time and its mechanism was probable that rhubarb tannins generated protein-precipitating reaction to the gastrointestinal mucosa due to its protein-precipitating action. CONCLUSIONS: The results confirmed that rhubarb had the diarrhoeogenic and antidiarrhoeal bidirectional effects due to the coexistence of anthraquinones and tannins. The bidirectional effects might be the reason or one of the reasons for the adverse effects of long-term use of rhubarb as a purgative.

Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients.

BACKGROUND & AIMS: Recent studies have suggested that CD4(+)CD25(+) regulatory T cells (Treg) are increased and linked to compromised immune responses in patients with hepatocellular carcinoma (HCC). This study attempted to further characterize CD4(+)CD25(+) forkhead/winged helix transcription factor (FoxP3)(+) Treg in blood, tumor, and nontumor liver tissues of HCC patients, and to understand how the Treg affects immune responses and contributes to disease progression. METHODS: A total of 123 HCC patients with chronic hepatitis B virus (HBV) infection, 21 HBV-related liver cirrhosis (LC) patients, and 47 normal controls were enrolled randomly. Flow cytometric, immunohistochemical, and immunosuppressive assays were used for analyses of properties of Treg. Multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. RESULTS: Circulating CD4(+)CD25(+)FoxP3(+) Treg frequency was increased significantly and correlated with disease progression in HCC patients. An abundant accumulation of Treg concurrent with significantly reduced infiltration of CD8(+) T cells was found in tumor regions compared with nontumor regions. Expression of granzyme A, granzyme B, and perforin was decreased dramatically in tumor-infiltrating CD8(+) T cells. Furthermore, Treg of HCC patients inhibited proliferation, activation, degranulation, and production of granzyme A, granzyme B, and perforin of CD8(+) T cells induced by anti-CD3/CD28 antibodies. Importantly, an increased quantity of circulating Treg was associated with high mortality and reduced survival time of HCC patients. CONCLUSIONS: Increased CD4(+)CD25(+)FoxP3(+) Treg may impair the effector function of CD8(+) T cells, promote disease progression, and represent both a potential prognostic marker and a therapeutic target for HBV-related HCC individuals.

[Study on chronical hepatitis B with treatment of integrative traditional Chinese and Western medicine].

OBJECTIVE: To study curative effect of chronical hepatitis B with treatment of integrative traditional Chinese and western medicine. METHOD: 115 cases of HBeAg and/or HBVDNA positive chronical hepatitis B were randomly divided into two groups in control. The first group treated by traditional Chinese medicine (TCM)-Fufang Huangqi granule and the second treated by intergrative traditional Chinese and western medicine (ICWM)-Fufang Huangqi granule and lamivudine for at least 24 weeks. RESULT: The positive rate of HBVDNA at 12, 24 weeks, and the positive rate of HBeAg at 24 weeks in TCM are markedly lower than those of before treatment (P < 0.01). The positive rate of HBeAg and the positive rate of HBVDNA in ICWM are markedly lower than those of before treatment both at 12, 24 weeks (P < 0.01). The average values of HBVDNA are markly lower than before treatment in two groups at both 12,24 weeks (P < 0.01). At 12 weeks, the negative-turning rate of HBVDNA in the ICWM group is 79.17%, which shows significant difference in comparision with 40.00% in the TCM group (P < 0.01). The negative-turning rate of HBeAg in the ICWM group is 26.92%, which shows no significant difference in comparision with 32. 08% in the TCM group. At 24 weeks, the negative-turning rate of HBVDNA in the ICWM group is 85.71%, which shows significant difference in comparision with 50.00% in the TCM group (P < 0.01). The negative-turning rate of HBeAg in the ICWM group is 36.36%, which shows no significant difference in comparision with 28.57% in the TCM group. At 12 weeks,the total effective rate of the ICWM group is 96. 43%, which shows significant difference in comparision with 71.26% in the TCM group (P<0.01). At 24 weeks, the total effective rate of the ICWM group is 88. 00%, which shows significant difference in comparision with 67.61 % in the TCM group (P < 0.01). The average values of ALT and AST are markly improved than those of before treatment in two groups (P < 0.01). The average values of ALB is markly higher than before in TCM groups after 24 weeks treatment (P < 0.01). CONCLUSION: Fufang Huangqi granule integrated with lamivudine possesses a better effect for counteracting the hepatitis B virus and improving the liver functioin than only itself.