Stephania tetrandra and other related species of Menispermaceae are the major sources of the bis-benzylisoquinoline alkaloids tetrandrine (TET), fangchinoline (FAN), and cepharanthine (CEP). Although the pharmacological properties of these compounds include anticancer and anti-inflammatory activities, the antiviral effects of these compounds against human coronavirus (HCoV) remain unclear. Hence, the aims of the current study were to assess the antiviral activities of TET, FAN, and CEP and to elucidate the underlying mechanisms in HCoV-OC43-infected MRC-5 human lung cells. These compounds significantly inhibited virus-induced cell death at the early stage of virus infection. TET, FAN, and CEP treatment dramatically suppressed the replication of HCoV-OC43 as well as inhibited viral S and N protein expression. The virus-induced host response was reduced by compound treatment as compared with the vehicle control. Taken together, these findings demonstrate that TET, FAN, and CEP are potential natural antiviral agents for the prevention and treatment of HCoV-OC43 infection. Biomolecules 2019, 9, 696 2 of 16anticancer, anti-inflammatory, and anti-oxidative activities [6]. TET exhibits broad pharmacological actions that include anti-inflammatory effects as well as immunosuppressant and anticancer activities [5]. Several studies have reported the effects of TET against the infection of different types of viruses such as herpes simplex virus, dengue virus, and Ebola virus [7][8][9]; others have shown that FAN inhibits the replication of human immunodeficiency virus type 1 (HIV-1) [10] and that CEP possesses antiviral activities against HIV-1 [11] and herpes simplex virus type 1 [12]. Coronaviruses (CoVs) are enveloped, positive-sense, single-stranded RNA viruses that infect a broad range of animal species and cause multiple respiratory outcomes of varying severity, including the common cold, bronchiolitis, and pneumonia [13]. CoVs are subdivided into four genera (Alpha-, Beta-, Gamma-, and Delta-) [14]. Among the six CoVs isolated from humans [15], the World Health Organization declared that accelerated research and the development of antivirals for the treatment of emerging zoonotic viruses, including β-CoVs, Middle East respiratory syndrome-related coronavirus (MERS-CoV), and severe acute respiratory syndrome-related coronavirus (SARS-CoV), are urgently needed [16]. Since the mid-1960s, human coronavirus strains OC43 (HCoV-OC43; β-CoV) and 229E (α-CoV) have been considered as mostly responsible for the common cold [17,18]. Notably, HCoV-OC43, which is the most prevalent subtype of HCoV [19], is responsible for up to 30% of respiratory infections and can cause repeated reinfections throughout life [20,21]. Moreover, HCoV-OC43 is most closely related to SARS-CoV and MERS-CoV, and shares several functional properties with both [22,23]. Due to the similarities with SARS-CoV and MERS-CoV, HCoV-OC43 has been used as an alternative model for research of these emerging viral strains to avoid the limitation of the requirement fo...

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Numerous transgenic mouse models for Alzheimer's disease (AD) have been generated to recapitulate the histological pathogenesis and behavioral phenotypes of AD brain. However, none of the existing models exhibits the full spectrum of AD symptoms, nor have all of the traits mimicked by the developed animal models been successfully represented within a single mouse line, indicating that the development of transgenic lines showing new features of the AD-like brain should be explored. Here we report on a transgenic mouse line, named Tg-APP (Sw, V717F)/B6, that expresses the human amyloid precursor protein (APP) containing the Swedish and the V717F Indiana mutations in the brains of inbred C57BL/6 mice, designed to eliminate the potential phenotypic variations attributed to the compound genetic backgrounds adopted in most AD mouse models. The Tg-APP (Sw, V717F)/B6 mice expressed the transgene transcript, in the heterozygote state, at a level of 2.6 +/- 0.1 fold higher than that of endogenous mouse APP. However, no Abeta-plaque deposition was produced in the brain of the Tg-APP (Sw, V717F)/B6 mice up to 18 months of age. The Tg-APP(Sw, V717F)/B6 mice at 13-15 months showed reduced expression of calbindin and c-Fos in the brain. The Tg-APP (Sw, V717F)/B6 mice at 11-14 months displayed decreased motor coordination, learning and memory deficits, and severely increased anxiety. These phenotypes were not observed in the Tg-APP (Sw, V717F)/B6 mice at 5-7 months. Microarray analysis revealed altered expression, in the amygdala of the Tg-APP (Sw, V717F)/B6 mice, of genes previously implicated in anxiety. Taken together, these results suggest that the transgenic APP, or its derivatives, produces the age-dependent pathophysiology of the AD-like brain and that the progressive cognitive impairment and anxiety induction can proceed in the absence of visible Abeta-plaque deposition.

Highlights Lycorine inhibited MERS-CoV, SARS-CoV, and SARS-CoV-2 infections. Lycorine directly inhibited MERS-CoV RdRp activity. Lycorine interacts with SARS-CoV-2 RdRp through hydrogen bonding. Lycorine is a non-nucleoside direct-acting antiviral against emerging coronavirus.

5-(2,6-difluorobenzyl)oxymethyl-5-methyl-3-(3-methylthiophen-2-yl)-1,2-isoxazoline derivative was synthesized, and its herbicidal activity was assessed under glasshouse and flooded paddy conditions. 5-(2,6-Difluorobenzyl)oxymethyl-5-methyl-3-(3-methylthiophen-2-yl)-1,2-isoxazoline demonstrated good rice selectivity and potent herbicidal activity against annual weeds at 125 g of a.i. ha(-1) under greenhouse conditions. Soil application of this compound showed complete control of barnyard-grass to the fourth leaf stage at 250 g of a.i. ha(-1). Field trials indicated that this compound controlled annual weeds rapidly with a good tolerance on transplanted rice seedlings by post-emergence and soil application. This compound showed a low mammalian and environmental toxicity in various toxicological tests.

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AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein 2) is a potent tumour suppressor that induces apoptosis in response to various oncogenic signals. AIMP2-DX2, an exon2-deleted splicing variant of AIMP2, is up-regulated in lung cancer and competitively suppresses the pro-apoptotic activity of AIMP2, resulting in tumorigenesis. In the present study we report that BC-DXI01, a synthetic compound, specifically reduces the cellular levels of AIMP2-DX2 through selective degradation of the AIMP2-DX2 mRNA transcript. We found that BC-DXI01-mediated cell death positively correlates with AIMP2-DX2 expression in the lung cancer cell lines tested. Administration of BC-DXI01 in a AIMP2-DX2-driven tumour xenograft mice model led to reduced tumour sizes and volumes of up to 60% in comparison with vehicle-treated mice group, consistent with decreases in AIMP2-DX2 transcript and protein levels. Taken together, our findings suggest that tumorigenic activity of AIMP2-DX2 can be controlled by the small chemical BC-DXI01, which can selectively suppress the AIMP2-DX2 mRNA transcript.

These results suggested that roflumilast exerts its anti-inflammatory effects in macrophages through a novel mechanism that involves the action of HO-1 and its product, CO.