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...

BackgroundBiomechanical phenomenon called “needle grasp” through the winding of connective tissue has been proposed as an action mechanism of acupuncture manipulation. The aim of the present study is to verify whether the needle grasp force affects the pain-relieving activity of acupuncture in the tail-flick latency (TFL) and the rat paw formalin tests.MethodsIn order to make different roughness on the acupuncture needle surface, the needles with 0.2 mm-diameter were scratched using silicon carbide sandpapers with the grit numbers of 600 (mild coarse) and 200 (extra coarse). The surface roughness and rotation-induced torque of the scratched needles were then measured by atomic force microscope and Acusensor®, respectively. Rat abdominal wall tissues including insertion site of acupuncture needle were excised after 5 unidirectional rotations of the needles having various degrees of roughness, and the morphological changes of connective tissues were analyzed using hematoxylin and eosin (H-E) staining. Finally, the effects of coarse needle surface on anti-nociception induced by twirling manipulation were tested in rat TFL and formalin test.ResultsIt was observed that the rougher the needle surface, the stronger the needle grasp force and thickness of subcutaneous connective tissue while rotating. TFL increased in proportion to surface roughness of the ground needles 10 min after acupuncture into the Zusanli acupoint (ST36) on rat’s legs. In the rat formalin test, the rougher needle also significantly exerted the larger analgesic effect during both early and late phases compared to non-ground normal needle.ConclusionSurface roughness of the acupuncture needle enhanced an anti-nociceptive activity of acupuncture therapy in rats, which partially supports the mechanical signaling theory through connective tissues in acupuncture manipulation.

The N-methyl-D-aspartate receptor (NMDAR) antagonists, phencyclidine (PCP), dizocilpine (MK-801), or ketamine, given subchronically (sc) to rodents and primates, produce prolonged deficits in cognitive function, including novel object recognition (NOR), an analog of human declarative memory, one of the cognitive domains impaired in schizophrenia. Atypical antipsychotic drugs (AAPDs) have been reported to improve declarative memory in some patients with schizophrenia, as well as to ameliorate and prevent the NOR deficit in rodents following scNMDAR antagonist treatment. While the efficacy of AAPDs to improve cognitive impairment in schizophrenia (CIS) is limited, at best, and controversial, single doses of all currently available AAPDs so far tested transiently restore NOR in rodents following scNMDAR antagonist treatment. Typical antipsychotic drugs (APDs), e.g. haloperidol and perphenazine, are ineffective in this rodent model, and may be less effective as treatments of some domains of CIS. Serotonergic mechanisms, including, but not limited to serotonin (5-HT)2A and 5-HT7 antagonism, 5-HT(1A), and GABA(A) agonism, contribute to the efficacy of the AAPDs in the scNMDAR antagonist rodent models, which are relevant to the loss of GABA interneuron/hyperglutamate hypothesis of the etiology of CIS. The ability of sub-effective doses of the atypical APDs to ameliorate NOR in the scNMDAR-treated rodents can be restored by the addition of a sub-effective dose of the 5-HT(1A) partial agonist, tandospirone, or the 5-HT7 antagonist, SB269970. The mGluR2/3 agonist, LY379268, which itself is unable to restore NOR in the scNMDAR-treated rodents, can also restore NOR when given with lurasidone, an AAPD. Enhancing cortical and hippocampal dopamine and acetylcholine efflux, or both, may contribute to the restoration of NOR by the atypical APDs. Importantly, co-administration of lurasidone, tandospirone, or SB269970, with PCP, to rodents, at doses 5-10 fold greater than those acutely effective to restore NOR following scNMDAR treatment, prevents the effect of scPCP to produce an enduring deficit in NOR. This difference in dosage may be relevant to utilizing AAPDs to prevent the onset of CIS in individuals at high risk for developing schizophrenia. The scNMDAR paradigm may be useful for identifying possible means to treat and prevent CIS.