Preventing filoviruses in the entry stage is an attractive antiviral strategy. Taking aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new aloperine derivatives were ...synthesized and evaluated for their anti-filovirus activities including ebola virus (EBOV) and marburg virus (MARV) using pseudotyped virus model. Structure-activity relationship (SAR) analysis indicated that the introduction of a 12N-dichlorobenzyl group was beneficial for the potency. Compound 2e exhibited the most potent anti-EBOV and anti-MARV effects both in vitro and in vivo. It also displayed a good pharmacokinetic and safety profile in vivo, indicating an ideal druglike feature. The primary mechanism study showed that 2e could block a late stage of viral entry, mainly through inhibiting cysteine cathepsin B activity of host components. We consider compound 2e to be a promising broad-spectrum anti-filovirus agent with the advantages of a unique chemical scaffold and a specific biological mechanism.
Aloperine derivative 2e was identified to exert a broad-spectrum anti-filovirus activity mainly through targeting a host protein cysteine cathepsin B to block a late stage of viral entry. Display omitted
•23 new aloperines were synthesized and evaluated for the anti-EBOV activity.•Compound 2e exhibited potent anti-EBOV/MARV effects both in vitro and in vivo.•Compound 2e displayed a good pharmacokinetic and safety profile in vivo.•Compound 2e could inhibit cat B activity to block the late stage of viral entry.
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•34 new monobactam derivatives are synthesized and evaluated for anti- Gram-negative bacteria.•Compounds 8p, 8r showed comparable activities with AZN, with MIC values of ...0.125–32 μg/mL.•They exhibited good synergistic effect on enzyme-producing G− bacteria combined with Avibactam.•Compounds 8p, 8r displayed excellent safety profiles both in vitro and in vivo.
Based on the structural characteristics of aztreonam (AZN) and its target PBP3, a series of new monobactam derivatives bearing various substituents on oxime residue were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative bacteria. Among them, compounds 8p and 8r displayed moderate potency with MIC values of 0.125–32 μg/mL against most tested Gram-negative strains, comparable to AZN. Meanwhile, the combination of 8p and 8r with avibactam as a β-lactamases inhibitor, in a ratio of 1:16, showed a promising synergistic effect against both ESBLs- and NDM-1-producing K. pneumoniae, with significantly reduced MIC values up to 8-fold and >256-fold respectively. Furthermore, both of them demonstrated excellent safety profiles both in vitro and in vivo. The results provided powerful information for further structural optimization of monobactam antibiotics to fight β-lactamase-producing resistant Gram-negative bacteria.
Host heat shock cognate 70 (Hsc70) protein is packaged into hepatitis C viral (HCV) particles as a structural component of the virus in the assembly process. It helps HCV RNA release into the ...cytoplasm in the next infection cycle. The goal of this study is to investigate whether chemically down‐regulating host Hsc70 expression could be a novel strategy to interrupt HCV replication. Compounds were screened with an Hsc70 messenger RNA (mRNA) assay. IMB‐DM122 was found to be an effective and safe inhibitor for Hsc70 mRNA/protein expression in human hepatocytes. IMB‐DM122 inhibited HCV replication through destabilization of Hsc70 mRNA, and the half‐life of host Hsc70 mRNA was reduced by 78% after the compound treatment. The Hsc70 mRNA 3′ untranslated region sequence is the element responsible for the effect of IMB‐DM122 on Hsc70 mRNA. The compound appears to be highly efficient in inhibiting Hsc70‐related HCV replication. Treatment of the HCV‐infected hepatocytes with IMB‐DM122 reduced the virion encapsidation of Hsc70, and therefore disrupted HCV replication and the infection cycle. IMB‐DM122 showed considerable good safety in vitro as well as in vivo with no indication of harmful effect on liver and kidney functions. Conclusion: Hsc70 might be a new drug target and mechanism to inhibit HCV proliferation. (HEPATOLOGY 2010;)
A series of novel N‐substituted sophocarpinic acid derivatives was designed, synthesized, and evaluated for their anti‐enteroviral activities against coxsackievirus type B3 (CVB3) and coxsackievirus ...type B6 (CVB6) in Vero cells. Structure–activity relationship analysis revealed that the introduction of a benzenesulfonyl moiety on the 12‐nitrogen atom in (E)‐β,γ‐sophocarpinic acid might significantly enhance anti‐CVB3 activity. Among the derivatives, (E)‐12‐N‐(m‐cyanobenzenesulfonyl)‐β,γ‐sophocarpinic acid (11 m), possessing a meta‐cyanobenzenesulfonyl group, exhibited potent activity against CVB3 with a selectivity index (SI) of 107. Furthermore, compound 11 m also showed a good oral pharmacokinetic profile, with an AUC value of 7.29 μM h−1 in rats, and good safety through the oral route in mice, with an LD50 value of >1000 mg kg−1; these values suggest a druggable characteristic. Therefore, compound 11 m was selected for further investigation as a promising CVB3 inhibitor. We consider (E)‐β,γ‐N‐(benzenesulfonyl)sophocarpinic acids to be a novel class of anti‐CVB3 agents.
Double‐bond drugs: N‐Substituted sophocarpinic acid derivatives were designed, synthesized, and evaluated for their activities against coxsackieviruses B3 (CVB3) and B6 (CVB6). Compound 11 m exhibited the most potent anti‐CVB3 effect, with an IC50 value of 2.5 μM (selectivity index: 107), which is much better than that of ribavirin.
B cell activating factor (BAFF) is a cytokine of tumor necrosis factor family mainly produced by monocytes and dendritic cells. BAFF can regulate the proliferation, differentiation, and survival of B ...lymphocytes by binding with BAFF-R on B cell membrane. Accumulating evidences showed that BAFF played crucial roles and was overexpressed in various autoimmune diseases such as systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). This suggests that BAFF may be a therapeutic target for these diseases. In the present study, we developed a BAFF therapeutic vaccine by coupling a T helper cell epitope AKFVAAWTLKAA (PADRE) to the N terminus of BAFF extracellular domains (PADRE-BAFF) and expressed this fusion protein in Escherichia coli. The purified vaccine can induce high titer of neutralizing BAFF antibodies and ameliorate the syndrome of complete Freund’s adjuvant (CFA) induced rheumatoid arthritis in rats. Our data indicated that the BAFF autovaccine may be a useful candidate for the treatment of some autoimmune diseases associated with high level of BAFF.
In this study, we investigated oxidative stress and tumor marker levels of polycyclic aromatic hydrocarbons (PAHs) in 136 coke oven workers and in 60 control subjects, and evaluated the correlation ...between oxidative stress and tumor marker levels. Questionnaires on basic demographic information were also administered. Significant differences in employment time and percentages of alcohol drinkers were observed between the control and exposed groups. PAH exposure was assessed using urinary 1-hydroxy-pyrene (1-OHP) levels and was found to be significantly higher in workers than in the controls. Significant differences (P<0.001) of MDA, GST, LDH, NSE, Cyfra21-1, and of SCC and TNF-a (P<0.0001 and P<0.05, P<0.001, respectively) levels were observed among controls and coke-oven workers, except for bottom coke oven workers. Associations between age and risk of increased TNF-a, smoking and increased GST activities, and drinking with increased MDA concentrations, were marginal (P=0.055, P=0.048, P=0.057, respectively). The association between smoking with MDA (P=0.004), NSE (P=0.005), SCC (P=0.004) and TNF-a (P<0.001), and drinking with TNF-a levels was significant (P=0.012). In addition, a significant positive correlation between oxidative stress and tumor markers was found in the present study. These results suggest that a synergistic increase of oxidative stress and tumor markers induced by PAHs may play a role in toxic responses for PAHs in coke oven workers.
With metabolic dysfunction-associated fatty liver disease (MAFLD) incidence and prevalence increasing, it is necessary to identify patients with advanced fibrosis (F3-F4 stages). We evaluated the ...performance of new biomarkers and algorithms for diagnosing advanced fibrosis in an Asian population.
Data from two Asian cohorts (including 851 biopsy-proven MAFLD 578 from Wenzhou, 273 from Hong Kong) were studied. The association between N-terminal propeptide of type 3 collagen (PRO-C3) and the histologic stage of liver fibrosis was analyzed by multivariable linear regression. The area under the receiver operating characteristic curve (AUROC) was used to test the diagnostic performance of serum PRO-C3 and the ADAPT score for advanced fibrosis and compared them to other established non-invasive tests.
Serum PRO-C3 levels increased progressively across liver fibrosis stages and correlated with advanced fibrosis (P < 0.001). The ADAPT score had an AUROC of 0.865 (95% confidence interval 0.829–0.901) for advanced fibrosis; the accuracy, sensitivity and negative predictive values were 81.4%, 82.2% and 96.1%, respectively. This result was better compared to that of PRO-C3 alone or other non-invasive fibrosis biomarkers (aspartate aminotransferase-to-platelet ratio index, Fibrosis-4, BARD, and NAFLD fibrosis score). In subgroup analyses (including sex, age, diabetes, NAFLD activity score, body mass index or serum alanine aminotransferase levels), the ADAPT score had good diagnostic performance.
PRO-C3 and the ADAPT score reliably exclude advanced fibrosis in MAFLD patients and reduce the need for liver biopsy.
•The N-terminal propeptide of type 3 collagen can be used for the staging fibrosis.•The ADAPT score has better diagnostic performance for identifying advanced fibrosis.•The ADAPT score can be used as new noninvasive tests for diagnosing advanced fibrosis.
In this paper, we explored the protective effect and physiochemical mechanism of He-Ne laser preillumination in enhancement of tall fescue seedlings tolerance to high salt stress. The results showed ...that salt stress greatly reduced plant growth, plant height, biomass, leaf development, ascorbate acid (AsA) and glutathione (GSH) concentration, the enzymatic activities, and gene expression levels of antioxidant enzymes such as catalase (CAT) and glutathione reductase (GR) and enhanced hydrogen peroxide (H
2
O
2
) content, superoxide radical (O
2
·−
) generation rates, membrane lipid peroxidation, relative electrolyte leakage, the enzymatic activities, and gene expression levels of superoxide dismutase (SOD), ascorbate peroxidase (APX), and peroxidase (POD), compared with controls. However, He-Ne laser preillumination significantly reversed plant growth retardation, biomass loss, and leaves development decay induced by salt stress. And the values of the physiochemical parameters observed in salt-stressed plants were partially reverted or further increased by He-Ne laser. Salt stress had no obvious effect on the transcriptional activity of phytochromeB, whereas He-Ne laser markedly enhanced its transcriptional level. Preillumination with white fluorescent lamps (W), red light (RL) of the same wavelength, or RL, then far-red light (FRL) had not alleviated the inhibitory effect of salt stress on plant growth and antioxidant enzymes activities, suggesting that the effect of He-Ne laser on improved salt tolerance was most likely attributed to the induction of phytochromeB transcription activities by the laser preillumination, but not RL, FRL or other light sources. In addition, we also utilized sodium nitroprusside (SNP) as NO donor to pre-treat tall fescue seedlings at the same conditions, and further evaluated the differences of physiological effects between He-Ne laser and NO in increasing salt resistance of tall fescue. Taken together, our data illustrated that He-Ne laser preillumination contributed to conferring an increased tolerance to salt stress in tall fescue seedlings due to alleviating oxidative damage through scavenging free radicals and inducing transcriptional activities of some genes involved in plant antioxidant system, and the induction of phytochromeB transcriptional level by He-Ne laser was probably correlated with these processes. Moreover, this positive physiochemical effect seemed more effective with He-Ne laser than NO molecule.
Heat-stress cognate 70 (Hsc70) is a host protein required for hepatitis B virus (HBV) replication, and oxymatrine (1) suppresses Hsc70 expression. Taking Hsc70 as a target against HBV, 22 analogues ...of 1 defined with substituents at position 1, 13, or 14 were synthesized and evaluated for their activity on Hsc70 mRNA expression. The SAR revealed that (i) the oxygen atom at the 1-position was not essential, (ii) increasing electron density on the ring D reduced the activity, and (iii) introducing a proper substituent at the 13- and/or 14-position(s), especially electron-withdrawing groups, might enhance the activity. Among the analogues, 6b possessing 13-ethoxyl afforded an increased activity in respect to 1. Importantly, it was active for either wild-type or lamivudine-resistant HBV, as its target is host Hsc70 but not viral enzymes. LD50 of 6b in mice was over 750 mg/kg in oral route. We consider compound 6b promising for further investigation.
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