Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival. The zona incerta (ZI) has been demonstrated to play important roles in fear learning and fear memory, as well as modulating auditory-induced innate defensive behavior. However, whether the neuronal subtypes in the ZI and specific circuits can mediate the innate fear response is largely unknown. Here, we found that somatostatin (SST)-positive neurons in the rostral ZI of mice were activated by a visual innate fear stimulus. Optogenetic inhibition of SST-positive neurons in the rostral ZI resulted in reduced flight responses to an overhead looming stimulus. Optogenetic activation of SST-positive neurons in the rostral ZI induced fear-like defensive behavior including increased immobility and bradycardia. In addition, we demonstrated that manipulation of the GABAergic projections from SST-positive neurons in the rostral ZI to the downstream nucleus reuniens (Re) mediated fear-like defensive behavior. Retrograde trans-synaptic tracing also revealed looming stimulus-activated neurons in the superior colliculus (SC) that projected to the Re-projecting SST-positive neurons in the rostral ZI (SC-ZIr^SST-Re pathway). Together, our study elucidates the function of SST-positive neurons in the rostral ZI and the SC-ZIr^SST-Re tri-synaptic circuit in mediating the innate fear response.
Mice ; Animals ; Zona Incerta/metabolism* ; Neurons/metabolism* ; Fear/physiology* ; Somatostatin/metabolism*

Licking behavior is important for water intake. The deep mesencephalic nucleus (DpMe) has been implicated in instinctive behaviors. However, whether the DpMe is involved in licking behavior and the precise neural circuit behind this behavior remains unknown. Here, we found that the activity of the DpMe decreased during water intake. Inhibition of vesicular glutamate transporter 2-positive (VGLUT2⁺) neurons in the DpMe resulted in increased water intake. Somatostatin-expressing (SST⁺), but not protein kinase C-δ-expressing (PKC-δ⁺), GABAergic neurons in the central amygdala (CeA) preferentially innervated DpMe VGLUT2⁺ neurons. The SST⁺ neurons in the CeA projecting to the DpMe were activated at the onset of licking behavior. Activation of these CeA SST⁺ GABAergic neurons, but not PKC-δ⁺ GABAergic neurons, projecting to the DpMe was sufficient to induce licking behavior and promote water intake. These findings redefine the roles of the DpMe and reveal a novel CeA^SST-DpMe^VGLUT2 circuit that regulates licking behavior and promotes water intake.

This paper introduced the basic definition, application scope, advantages and challenges of the master protocol, basket design, umbrella design and platform trial, and put forward the idea of using master protocol, basket design and umbrella design in Chinese medicine(CM) by considering the characteristics of CM and research experiences. The author pointed out that master protocol, basket design and umbrella design, as a high-efficiency research and design strategy, can be used in the clinical research on the treatment of the same disease with different therapies, the treatment of different diseases with the same therapy and the combination of diseases and CM syndromes. In particular, the exploration from the classification of CM syndromes can supplement the gaps in the cli-nical research on CM syndromes. In the application of such designs, it is also necessary to pay attention to their potential challenges and develop reasonable and feasible plans on research implementation, management and statistical analysis in advance to meet these challenges.
Dietary Supplements ; Medicine, Chinese Traditional ; Precision Medicine ; Records ; Research Design

Objective:To study the effects of different processing methods on the anti-gouty arthritis and cardiotoxicity of Aconiti Radix， and to explore the possible attenuation and synergism mechanism of these different processing methods. Method:The swelling degree of knee joint， levels of inflammatory factors ［interleukin （IL） -1β， IL-18， tumor necrosis factor （TNF）-α］ and the activities of liver energy metabolism-related enzymes ［Ca²⁺-Mg²⁺-adenosine triphosphatase （ATPase）， Na⁺-K⁺-ATPase， succinate dehydrogenase （SDH）］ in rats with gouty arthritis were used as indicators to evaluate the effects of pharmacopoeia steaming Aconiti Radix， pharmacopoeia boiling Aconiti Radix， Jianchang faction processed Aconiti Radix， Zhang faction processed Aconiti Radix and raw Aconiti Radix. The activity of creatine kinase （CK）， lactate dehydrogenase （LDH） and the content of B-type natriuretic peptide （BNP） were used as indexes to evaluate the cardiotoxicity of Aconiti Radix and its different processed products. Result:In the anti-gouty arthritis test， compared with the blank group， the knee joint of the model group was significantly swollen （P<0.01）， the levels of IL-1β， IL-18， and TNF-α in serum were significantly increased （P<0.01）， and the Ca²⁺-Mg²⁺-ATPase activity was significantly decreased （P<0.01）. Compared with the model group， raw Aconiti Radix and the four processed products could reduce knee joint swelling and decrease IL-1β， IL-18， and TNF-α levels in serum of rats. The activity of Ca²⁺-Mg²⁺-ATPase in the liver of rats from the pharmacopoeia steaming Aconiti Radix group was significantly higher than that in the model group （P<0.01）， and there was no statistical difference in other groups. In the cardiotoxicity test， compared with the blank group， the activities of CK and LDH were significantly increased and the level of BNP was significantly increased in the raw Aconiti Radix group and the pharmacopoeia steaming/boiling Aconiti Radix groups （P<0.01）. In terms of LDH activity and BNP content， the Zhang faction and Jianchang faction processed Aconiti Radix groups were significantly lower than those in the raw Aconiti Radix group （P<0.01）. In the CK activity， the Zhang faction processed Aconiti Radix group was significantly lower than that in the raw Aconiti Radix group （P<0.01）. Conclusion:Raw Aconiti Radix and the four processed products have certain anti-inflammatory effects， but there are some differences among different indicators. There are significant differences in cardiotoxicity between the raw products and processed products of Aconiti Radix， and the cardiotoxicity of Jianchang faction and Zhang faction processed products was the weakest.

This research is to predict anti-Alzheimer's disease active constituents on the target of acetylcholinesterase(AChE) from Glycyrrhizae Radix et Rhizoma with the help of pharmacophore and molecular docking. AChE ligand-based pharmacophore model was set up and the molecular library of the constituents from Glycyrrhizae Radix et Rhizoma were established by collecting literature. Then the constituents from Glycyrrhizae Radix et Rhizoma were screen for the potential AChE inhibitory potency in silico through matching with the best pharmacophore model. The flexible docking was used to evaluate the interactions between compounds screened from pharmacophore model and AChE protein(PDB ID:4 EY7). The interactions were expressed including but not limited to CDOCKER interaction energy, hydrogen bonds and non-bonding interactions. The molecular library of Glycyrrhizae Radix et Rhizoma contains 44 chemical constituents. As for the pharmacophore model, six kinds of potential AChE inhibitory constituents from Glycyrrhizae Radix et Rhizoma were considered to be the promising compounds according to the results of searching 3 D database of pharmacophore model. The molecular docking was possessed and the interaction patterns were given to show the detail interactions. The compounds screening from the pharmacophore model were consistent with the existing studies to some degree, indicating that the virtual screen protocols of AChE inhibitory constituents from Glycyrrhizae Radix et Rhizoma based on pharmacophore and molecular docking was reliable.
Drugs, Chinese Herbal ; Glycyrrhiza ; Molecular Docking Simulation ; Rhizome ; Triterpenes

Lanqin Oral Liquid is a Chinese patent medicine which contains Isatidis Radix, Scutellariae Radix, Gardeniae Fructus, Phellodendri Chinensis Cordex and Sterculiae Lychophorae Semen. It is known for the pharmaceutical effect on the upper respiratory tract infection as it is beneficial for relieving the swelling of pharyngeal. In terms of Chinese medicine, it offers a clearing action on heat and toxic materials. According to the principle of Chinese medicine, different diseases can be treated by the same therapy as long as they have the same syndrome. Based on this unique diagnosis and treatment approach, Lanqin Oral Liquid was applicable to diseases with syndrome of excessive heat in lung and stomach. It was therefore commonly be used in the therapeutic approach towards hand, foot and mouth disease as well. However, no systematic evaluation had yet been done to verify this Chinese patent medicine on the efficacy and clinical safety for the disease. In order to achieve the manner of evidence-based medicine, this study had adopted a systematic review and Meta-analysis to evaluate the efficacy and safety of Lanqin Oral Liquid in the treatment of hand, foot and mouth disease. All related randomized controlled trials(RCT) were searched in the following data bases: CNKI, WanFang, VIP, SinoMed, Cochrane Library and PubMed. Based on the method provided by the Cochrane collaboration, the study assessed the quality of papers selected and RevMan 5.3 software was used to perform Meta-analysis. Totally 24 studies were included with 3 491 sample size, which 1 826 cases were treatment group and 1 665 cases were control group. From the results of Meta-analysis, the total effective rate of combination of Lanqin Oral Liquid and Western medicines shown better than Western medicine alone in the treatment for hand, foot and mouth di-sease, but mild adverse event were also found(RR=1.20,95%CI[1.16,1.23],P<0.000 01). Incidence of adverse reaction between experimental and control group was statistically insignificant(RR=1.16, 95%CI[0.79, 1.70], P=0.45). No conclusion was able to made in terms of the remission time of clinical symptoms, as the studies included were not qualified for Meta-analysis. As a matter of fact, the number of existing studies related to the Lanqin Oral Liquid were limited with poor quality as well. In other words, high quality studies were essential to further evaluate the efficacy and safety of Lanqin Oral Liquid.
Drugs, Chinese Herbal ; Hand, Foot and Mouth Disease ; Humans ; Medicine, East Asian Traditional ; Nonprescription Drugs ; Research Design

Aconiti Radix is a kind of medicinal material with great toxicity, which has more than 2 000 years of clinical application history, in the folk, there are often poisoning accidents caused by improper processing. The main processing purpose of Aconiti Radix in the early period was to reduce the toxicity with simple procedure and single excipient. Since the Song dynasty, with the deepening of physicians' cognition of processing and the theory of medicinal properties, the application of procedures and materials in the processing of Aconiti Radix began to become complicated, and the scope of clinical application was further expanded. In modern times, the processing technology of Aconiti Radix is mainly based on steaming and boiling, which is quite different from the traditional processing method with multiple materials and multiple processes. Based on the characteristics of many kinds of materials and processes, this paper discusses the change in processing methods of Aconiti Radix from the perspective of excipients and processes, as well as modern processing research, in order to lay a scientific foundation for exploring the effects of many kinds of materials and processes on the quality of Aconiti Radix and revealing its processing mechanism, and provide basis and reference for establishing a more reasonable and scientific processing method for Aconiti Radix in the future.

To explore therapeutic effect of acupuncture combined electrical stimulation on aged patients with post‐stroke depression .Methods : A total of 78 patients with post‐stroke depression were randomly and equally divided into routine treatment group (received health education based on routine treatment ) and combined treatment group (received acupuncture combined low‐frequency electrical stimulation based on routine treatment group ).After four‐week treatment , score of Hamilton rating scale for depression (HAMD) and therapeutic effect were compared between two groups .Results : Compared with before treatment , there was significant reduction in HAMD score in two groups after treatment ;compared with routine treatment group after treatment , there was significant reduction in HAMD score [(19.72 ± 2. 04) scores vs.(14. 94 ± 1. 86) scores] in combined treatment group , P＝0. 001 all.To‐tal effective rate of combined treatment group was significantly higher than that of routine treatment group (87.18% vs.64.1%, P＝0.018).Conclusion : Acupuncture combined low‐frequency electrical stimulation possesses significant therapeutic effect on post‐stroke depression , which is worthy of clinical application .

In 2013,China pharmaceutical regulatory department issued guiduance on postmarketing drug safety monitoring for industry. It aimed to encourage industry to carry out postmarketing drug safety monitoring including hospital-based intensive monitoring of postmarketing Chinese patent medicine. Subsequently,more and more such kind of studies have been performed all over China. However,in view of the current situation in this field,the development of hospital-based intensive monitoring of postmarketing Chinese patent medicine lacks standardization,such as unreasonable design,omission of reports about adverse drug reactions,inadequate process of quality control,non-standardized interpretation of adverse reactions,etc. Therefore,it is necessary to formulate relevant technical specifications to guide this area. The developing of this technical specification refered to the international post-marketing safety monitoring model and advanced design concepts and methods. We developed it under the guidance of relevant laws,regulations and technical documents in China. Meanwhile the characteristics of Chinese patent medicines and the real situation in this area were considered. The aim of this technical specification is to obtain the incidence,type,degree and clinical manifestation of adverse drug reactions of Chinese patent medicines,to find new risk signals of adverse reactions,to identify risk factors,and to provide a basis for the formulation of risk management and control plans. This specification has been approved by China association of Chinese medicine which is numbered T/CACM011-2016.
Adverse Drug Reaction Reporting Systems ; China ; Hospitals ; Medicine, Chinese Traditional ; Nonprescription Drugs ; Product Surveillance, Postmarketing