Electrochemical detection of the oxidative damage of a potential pyrimido[5,4-g]pteridine-derived antitumor agent toward DNA.

In this work, we design and synthesize 2,2'-(7,9-dimethyl-2,4,6,8-tetraoxo-6,7,8,9-tetrahydropyrimido[5,4-g]pteridine-1,3(2H,4H)-diyl)bis(N,N-bis(2-chloroethyl)acetamide) (PT-MCA) as a novel DNA intercalator and potential antitumor agent. Electrochemical analysis reveals the redox process of PT-MCA on the electrode surface. The bioelectrochemical sensors are obtained by modifying the surface of GCE with calf thymus DNA (ctDNA), poly (dG), poly (dA), and G-quadruplex, respectively. The DNA oxidative damage induced by PT-MCA is investigated by comparing the peak intensity change of dGuo and dAdo and monitoring the peaks of the oxidation products of guanine and/or adenine (8-oxoGua and/or 2,8-oxoAde). UV-vis absorption and fluorescence spectra and gel electrophoresis are further employed to understand the intercalation of PT-MCA into DNA base pairs. Moreover, PT-MCA is proved to exhibit stronger anti-proliferation activity than mitoxantrone against both 4T1 and B16-F10 cancer cells. At last, the oxidative damage of PT-MCA toward ctDNA is not interfered by the coexistence of ions and also can be detected in real serums.

[CiteSpace knowledge map analysis of Angong Niuhuang Pills in recent twenty years].

Angong Niuhuang Pills, a classical formula in traditional Chinese medicine, are lauded as one of the "three treasures of febrile diseases" and have been widely used in the treatment of diverse disorders with definite efficacy. However, there is still a lack of bibliometric analysis of research progress and development trend regarding Angong Niuhuang Pills. Research articles on Angong Niuhuang Pills in China and abroad(2000-2022) were retrieved from CNKI and Web of Science. CiteSpace 6.1 was used to visualize the key contents of the research articles. In addition, the research status of Angong Niuhuang Pills was analyzed by information extraction to allow insight into the research trends and hotspots about Angong Niuhuang Pills. A total of 460 Chinese articles and 41 English articles were included. Beijing University of Chinese Medicine and Sun Yat-Sen University were the research institutions that have published the largest amount of research articles in Chinese and English. The keyword analysis showed that the Chinese articles focused on cerebral hemorrhage, stroke, neurological function, coma, cerebral infarction, craniocerebral injury, and clinical application, while the English articles focused on the mechanisms of cerebral ischemia, stroke, heavy metal, blood-brain barrier, and oxidative stress. Stroke, blood-brain barrier, and oxidative stress were presumably the research hotspots in the future. At present, the research on Angong Niuhuang Pills is still in the developing stage. It is necessary to highlight the in-depth research on the active components and mechanism of action and carry out large-scale randomized controlled clinical trials to provide references for the further development and application of Angong Niuhuang Pills.

[Analysis of medication regularity of classical prescription in treatment of COPD based on multi-target efficacy evaluation system of Chinese medicine].

Effective drugs for chronic obstructive pulmonary disease(COPD), a complex chronic lung disease, have long been difficultly determined, while traditional Chinese medicine(TCM) has played a critical effect in the treatment of such disease. A new approach for the prediction based on data analysis by integrating TCM basic theories and modern science is urgently needed apart from clinical experiments. In this study, an efficacy evaluation system of COPD was established based on the multi-target efficacy evaluation system of Chinese medicine to analyze the medication regularity and characteristics, such as efficacies, properties, meridian tropism,and core combinations of Chinese medicines. The characteristics of classical prescriptions in the intervention of COPD were explored from modern pharmacology. The results showed that the Chinese medicines in the classical prescriptions in the treatment of COPD were dominated by heat-clearing, phlegm-resolving, dampness-dispelling, exterior-releasing, deficiency-tonifying, and interior-warming drugs. Among them, dampness-dispelling, interior-warming, and heat-clearing drugs resulted in higher perturbation efficiency in the disease network than some western medicines on the market, suggesting that these drugs possessed better efficacies in the treatment of COPD. In the classic prescriptions, warm-heat drugs were equivalent to cold-cool drugs in number, while the proportion of warm-heat drugs gradually raised with the increase in the perturbation efficiency. Additionally, core combinations in the classical prescriptions,such as heat-clearing/heat-clearing, dampness-dispelling/dampness-dispelling, and phlegm-resolving/heat-clearing, could achieve better efficacy for COPD. The present study preliminarily screened out the efficacies of Chinese medicines in the treatment of COPD based on scientific data through the multi-target efficacy evaluation system to explore the effect of Chinese medicine on COPD from modern pharmacology, explain the mechanism of TCM treatment of lung diseases, and provide references for the development of drugs targeting COPD.

[Analysis of potential role of Chinese classic prescriptions in treatment of COVID-19 based on TCMATCOV platform].

With the global outbreak of coronavirus disease 2019(COVID-19), screening of effective drugs has became the emphasis of research today; furthermore, screening of Chinese classic prescriptions has became one of the directions for drug development. This study analyzed the application of classic prescriptions in the diagnosis and treatment schemes based on the Diagnosis and Treatment Schemes for Coronavirus Disease at the country, provincial and municipal levels, and further explored its disrobing effect on COVID-19 disease severe phase network, and selected representative prescriptions for core target screening and gene enrichment analysis, so as to reveal its mechanism of action. Among them, 13 prescriptions were found to be used for 10 times or more, including Maxing Shigan Tang, Yinqiao San, Shengjiang San, Dayuan Drink, Xuanbai Chengqi Decoction. In addition, the COVID-19 efficacy prediction analysis platform(TCMATCOV platform) was used to calculate the network disturbances of the Chinese classic prescriptions involved. Based on the prediction results, 68 classic prescriptions were assessed on the COVID-19 disease network robustness disturbance. The average disturbance scores for the interaction confidence scores were ranked to be 0.4, 0.5, and 0.6 from the highest to the lowest. There were 7 prescriptions with a score of 17 or more, and 50 prescriptions with a score of 13 or more. Among them, the top three prescriptions were Ganlu Xiaodu Dan(18.19), Lengxiao Wan(17.74), and Maxing Shigan Tang(17.62). After further mining the action targets of these three prescriptions, it was found that COVID-19 disease-specific factors Ccl2, IL10, IL6 and TNF were all the targets of three prescriptions. Through the enrichment analysis of the biological processes of the core targets, it was found that the three prescriptions may prevent the development of the disease by affecting cell-to-cell adhesion, cytokine-mediated signaling pathway, and chronic inflammatory responses to COVID-19 at the severe phase. This study showed that the TCMATCOV platform could evaluate the disturbance effect of different prescriptions on the COVID-19 disease network, and predict potential effectiveness based on the robustness of drug-interfered pneumonia disease networks, so as to provide a reference for further experiments or clinical verification.

[Research progress of intervention of Chinese herbal medicine and its active components on human coronavirus].

The outbreak caused by 2019 novel coronavirus(2019-nCoV) is still spreading, posing a great threat to the safety and health of general population. However, there have not been any effective drugs for treatment, with symptomatic treatment and prevention prevailing. The treatment plans of severe acute respiratory syndrome(SARS) and Middle East respiratory syndrome(MERS) are often used for reference in clinic. The advantages of traditional Chinese medicine(TCM) in treating SARS and MERS are that it can intervene and block the progression of disease in early stage, significantly reduce symptoms, shorten the treatment duration of patients, reduce complications and side effects caused by hormone therapy. The coronavirus disease 2019(COVID-19) belongs to the category of TCM epidemic diseases. Chinese patent medicines and prescriptions in medical observation and clinical treatment were recommended in the "pneumonia diagnosis and treatment plan for new coronavirus infection"(trial version fifth) of the National Health Commission of the People's Republic of China. Qingfei Paidu Decotion was recommended for the treatment of COVID-19 by the National Health Commission of the People's Republic of China and National Administration of Traditional Chinese Medicine. TCM shows good clinical efficacy and great potential in the treatment of COVID-19. Previous studies of TCM have shown broad-spectrum antiviral activity, providing a variety of sources for the discovery of new antiviral drugs. In this paper, we reviewed traditional Chinese medicines and its active ingredients in the hope of bringing novel inspirations to the drug screening and clinical treatment for COVID-19.

[Possible pharmaceutical effect and active components in different parts of Eucommia ulmoides based on network pharmacology].

The difference in pharmacological activities and active components between leaves, barks and flowers of Eucommia ulmoides(EU) are still unclear. However, clarifying the differences in pharmacological effects of different parts of EU is of great significance for the development of EU products, and their corresponding active components provide basis for quality control of different parts of EU. Based on the chemical compositions of different parts of EU, integrated strategy of target prediction and target analysis of the compounds was used to investigate the difference in the pharmacological effects of leaves, barks and followers. The "component-target-function" association network was constructed to mine the specific material basis corresponding to specific efficacy of different parts of EU. In this study, the author found that EU may have the activities of anti-oxidation, neuromodulation, blood pressure regulation, myo-cardial expansion, and anti-apoptosis according to target prediction and function analysis. However, the effects of different parts of EU were different. Leaves were involved in the process of bone development such as osteoblast differentiation and bone mineralization in a specific way. In addition, the leaves may affect the process of bone development by regulating the metabolism of vitamin D and affecting the absorption of calcium. Leaves may also specifically act on estrogen and estradiol response processes where estrogen receptors were involved. Regarding its protective function for the liver, leaves may play a role by regulating vitamin A-related pathways. As compared with leaves, the specific pharmacological effects of barks may be related to the development of the urinary system. Flowers specifically participate in functions related to pain sensation, glutamate signaling pathway, and excitatory postsynaptic potential. Based on the hie-rarchical network of "component-target-pathway", we further found that specific activities of different parts of EU were inseparable from its specific chemical compositions. Phenylpropanoids, terpenoids and rings, iridoids, flavonoids and other components which are specific in leaves can target the specific effects of leaves, while the flavonoids in barks and the quinones in flowers may be the material basis for their respective specific effects. The prediction of the activities of different parts of EU provides a new basis for the focuses and differences in subsequent Eucommia product development. At the same time, the material basis research based on differential efficacy also provides a basis for the quality control of Eucommia differentiated products.

[Research advances in chemical constituents and pharmacological activities of different parts of Eucommia ulmoides].

To date, 205 compounds have been identified from different medicinal parts of Eucommia ulmoides, including lignans, iridoid terpenoids, phenols, flavonoids, terpenoids and steroids, polysaccharides and others. Their pharmacological effects include blood pressure-lowering, blood sugar-lowering, blood lipids-regulating, prevention of osteoporosis, anti-inflammation, liver protection, anti-cancer and so on. Their efficacy and mechanism from different parts are slightly different. In this paper, the chemical composition, pharmacological action and mechanism of different parts of E. ulmoides were systematically summarized, as well as its quality control and processing research, to provide theoretical basis for further rational development and utilization of E. ulmoides.

[TCMATCOV--a bioinformatics platform to predict efficacy of TCM against COVID-19].

There is urgent need to discover effective traditional Chinese medicine(TCM) for treating coronavirus disease 2019(COVID-19). The development of a bioinformatic tool is beneficial to predict the efficacy of TCM against COVID-19. Here we deve-loped a prediction platform TCMATCOV to predict the efficacy of the anti-coronavirus pneumonia effect of TCM, based on the interaction network imitating the disease network of COVID-19. This COVID-19 network model was constructed by protein-protein interactions of differentially expressed genes in mouse pneumonia caused by SARS-CoV and cytokines specifically up-regulated by COVID-19. TCMATCOV adopted quantitative evaluation algorithm of disease network disturbance after multi-target drug attack to predict potential drug effects. Based on the TCMATCOV platform, 106 TCM were calculated and predicted. Among them, the TCM with a high disturbance score account for a high proportion of the classic anti-COVID-19 prescriptions used by clinicians, suggesting that TCMATCOV has a good prediction ability to discover the effective TCM. The five flavors of Chinese medicine with a disturbance score greater than 1 are mainly spicy and bitter. The main meridian of these TCM is lung, heart, spleen, liver, and stomach meridian. The TCM related with QI and warm TCM have higher disturbance score. As a prediction tool for anti-COVID-19 TCM prescription, TCMATCOV platform possesses the potential to discovery possible effective TCM against COVID-19.

[Nutritional support in children with pneumonia on mechanical ventilation by short-peptide enteral nutrition formula].

OBJECTIVE: To observe the incidence of malnutrition and nutritional risk in children with pneumonia on mechanical ventilation in the pediatric intensive care unit (PICU), and to explore the nutritional support effect of short-peptide enteral nutrition formula. METHODS: A total of 68 children with severe pneumonia who were hospitalized in the PICU from October 2017 to October 2018 and required mechanical ventilation were enrolled for a prospective randomized controlled study. The children were randomly divided into a control group and an experimental group. Through the nasogastric feeding tube, the experimental group received the short-peptide enteral nutrition formula, and the control group received the intact-protein enteral nutrition formula. The weight-for-age Z score, STRONGkids nutritional risk score, and pediatric critical illness score of the two groups were evaluated. The serum levels of total protein, albumin, and prealbumin (PA) on admission and before discharge were measured. The gastrointestinal tolerance and clinical outcome indicators of the two groups were observed. RESULTS: Among the 68 mechanically ventilated children, 26 (38%) had malnutrition, including moderate malnutrition (10 cases, 15%) and severe malnutrition (16 cases, 24%); 10 cases (15%) had malnutrition at discharge. Sixty-three children (93%) had nutritional risk, including moderate nutritional risk in 21 cases and high nutritional risk in 42 cases. The moderate and high nutritional risk rates of the critical and extreme critical groups were significantly higher than those of the non-critical group (P<0.05). Compared with the control group, the experimental group had significantly shorter duration of mechanical ventilation and total length of hospital stay, significantly higher serum PA level and weight growth rate, and significantly better gastrointestinal tolerance (P<0.05). There were no significant differences in the incidence of ventilator-associated pneumonia and disease outcome between the two groups (P>0.05). CONCLUSIONS: The detection rates of malnutrition and nutritional risk in children with pneumonia on mechanical ventilation are relatively high. Short-peptide enteral nutrition formula can help improve their treatment outcome and are more suitable for nutritional support in critically ill children on mechanical ventilation.

[Molecular mechanism of Shuguan Granules in treating angina based on integrative pharmacology].

The paper analyzed the combined administration of traditional Chinese medicine Shuguan Granules, and studied its six plant herbs, namely Polygoni Multiflori Radix, Salviae Miltiorrhizae Radix et Rhizoma, Polygonati Rhizoma, Chuanxiong Rhizoma, Epomedii Folium, and Carthami Flos by network pharmacology analysis, in order to define chemical constituents and drugs targets through integrated pharmacology platform. Based on the results, indications of Shuguan Granules were collected through the ETCM database. Therefore, the present study could determine the potential optimal indications of the drug. The results showed that chest apoplexy was the main traditional Chinese medicine(TCM) symptom treated by Shuguan Granules, whose monarch drug was Salviae Miltiorrhizae Radix et Rhizoma. Network pharmacology analysis found that the target enrichment results of Shuguan Granules were related to the indications of coronary heart disease, angina and atherosclerosis. According to the indications, angina may be the best indication for Shuguan Granules. The 229 components in Shuguan Granules involved a total of 109 core targets, of which TNF and MMP9 were the direct targets to the angina disease. In addition, Shuguan Granules could also indirectly intervene in the progression of angina through MAPK, NFKB, GF and other targets. The main pathways involving angina pectoris are PI3 K-Akt signaling pathway, RAS signaling pathway, TNF signaling pathway, Estrogen signaling pathway and glycolysis/gluconeogenesis, which can intervene in many aspects of angina, such as inflammatory reaction, blood lipid metabolism and vasodilation.

[Nutritional assessment and clinical application of nutritional risk screening tools in critically ill children].

OBJECTIVE: To investigate the nutritional status of critically ill hospitalized children and to explore the value of nutritional risk screening tools in the nutritional risk assessment. METHODS: The clinical data of 211 critically ill children who were admitted to the pediatric intensive care unit from November 2017 to April 2018 were collected to evaluate their nutritional status on admission and at discharge. Two nutritional risk screening tools, STRONGkids and PYMS, were used for nutritional risk screening in the 211 children. RESULTS: Among the 211 patients, 68 (32.2%) were found to have malnutrition on admission, with 34 cases each of moderate and severe malnutrition. Moderate or high nutritional risk was found in 154 cases (73.0%) with STRONGkids and 165 cases (78.2%) with PYMS. Using weight-for-age Z-score as the gold standard to evaluate the efficacy of the two nutritional risk screening tools, the areas under the receiver operating characteristic curves of STRONGkids and PYMS were 0.822 and 0.759 respectively. Both tools had a significant clinical value in screening for malnutrition (P<0.05), but there was no significant difference in clinical efficacy between them (P>0.05). With the optimal cut-off value of 3 points, the sensitivities of STRONGkids and PYMS for screening of malnutrition were 92.1% and 76.2% respectively. The children with moderate or high nutritional risk on admission had a significantly poorer prognosis than those with low nutritional risk (P=0.014 and 0.001 respectively). The children with severe malnutrition had a significantly poorer prognosis than those with normal nutrition (P=0.0009). CONCLUSIONS: The detection rates of malnutrition and nutritional risk are high in critically ill children. Malnutrition/high nutritional risk is related to a poor prognosis. Both STRONGkids and PYMS have a clinical value for nutritional risk screening in critically ill children, and they have similar clinical efficacy; however, STRONGkids is more sensitive.

[Compatibility law of Baizhi formulae and molecular mechanism of core herbal pair "Baizhi-Chuanxiong"].

By using the traditional Chinese medicine inheritance support system (TCMISS) in this study, the prescription rules of Baizhi formulae were analyzed and the core herbal pair "Baizhi-Chuanxiong" was obtained. Through the systemic analysis of prescription rules of "Baizhi-Chuanxiong" and combined with the pharmacology thinking of "Baizhi-Chuanxiong" in treating headache, the paper was aimed to find out the combination rules containing Baizhi andits molecular mechanisms for treating headaches, and provide the theory basis for further research and reference of Baizhi and its formula. Totally 3 887 prescriptions were included in this study, involving 2 534 Chinese herbs. With a support degree of 20% in analysis, 16 most commonly used drug combinations were screened, which were mainly used to treat 15 types of diseases. Baizhi was often used to treat headache, and the core combination "Baizhi-Chuanxiong" was also often used to treat, consistent with ancient record. A chemical database was established; then the headache and migraine disease targets were retrieved and added in the database to build up the "compounds-targets-pathways "core network of "Baizhi-Chuanxiong" by the internet-based computation platform for IP of TCM (TCM-IP). TCM-IP was then applied to study the molecular mechanism of "Baizhi-Chuanxiong" treatment of headache. The results suggested that37 chemical compounds in the core combination "Baizhi-Chuanxiong" were closely related with headache treatment by adjusting serotonin levels or applying to inflammation-related targets and energy metabolism pathways such as purine metabolism, pyruvate metabolism, fatty acid degradation, carbon metabolism and gluconeogenesis.

[Study on Yueju Wan for "different diseases with same treatment" based on integrative pharmacology].

The traditional Chinese medicine prescription Yueju Wan has the function of regulating qi-flowing for activating stagnancy and resolving food stagnation, which is now used for the treatment of depression and gastrointestinal related diseases. In this study, an integrative pharmacological method was adopted to predict the targets and pathways of Yueju Wan and explore its molecular mechanism for depression and gastrointestinal dysfunction with the same treatment. First, disease targets were collected from Human Phenotype Ontology database, 201 targets related to depression and 474 targets related to gastrointestinal dysfunction, including 95 common targets of these two. Then, the integrative pharmacology platform of traditional Chinese medicine (TCMIP) was used to predict and analyze the drug targets, GO function, KEGG pathway, core targets network of Yueju Wan and heterogeneous network of TCM-chemical components-key drug targets-pathway. According to the integrative analysis, it is found that ATP1A1, KRAS, and PRKAA1 were key targets, and neuron apoptotic process, neurotrophin signaling pathway, serotonergic synapse and regulation of nitric-oxide synthase activity were key pathways which played important roles in molecular mechanism of Yueju Wan for depression and gastrointestinal dysfunction. In conclusion, speculated serotonergic synapse and regulation of nitric-oxide synthase activity maybe the common process in depression and gastrointestinal dysfunction. This paper provided an overall understanding on Yueju Wan based on TCMIP, helping to elucidate the mechanism of the same treatment for different diseases, depression and gastrointestinal dysfunction.

[Molecular mechanism of Tibetan medicine Rhodiola crenulata prevents oxidative stress through network pharmacology].

In this study, a computer-based network pharmacology approach was applied to investigate the potential mechanism and important components of Rhodiola crenulata in the protection of H9c2 cells against hydrogen peroxide (H2O2)-induced oxidative stress. The intestinal absorption liquid of R. crenulata enhanced the cell viability, maintained cell morphology and inhibited cell apoptosis in the H2O2-induced oxidative stress in H9c2. Then, computer-based network pharmacology was used to analyze the relevant mechanism. A total of 133 oxidative stress-related compounds were screened out; and 26 of them occupied the top 20%, and all of the compounds enriched in 43 oxidative stress-related key targets. Finally, a "compound-target-pathway-function" network was constructed. Based on the analysis of the network pharmacology, R. crenulata protected H9c2 cells against H2O2-induced oxidative stress probably by affecting apoptosis-related processes, such as cell death, nitric oxide metabolism, oxidative stress, mitochondrial mechanism, redox process, redox-related enzyme activty and other oxidative stress-related process. And salidroside, ethyl gallate and catechins, which were the main components of R. crenulata, played an important role in this process. Therefore, the potential mechanism and important components of R. crenulata revealed the protective effect on oxidative stress. This study shows a multi-component, multi-target and overall regulation effect of R. crenulata on the oxidative stress, and provides a reliable reference for subsequent systematic experimental studies for the pharmacodynamic material foundation and mechanism of action R. crenulata.

[Exploiture and application of an internet-based Computation Platform for Integrative Pharmacology of Traditional Chinese Medicine].

Recently, integrative pharmacology(IP) has become a pivotal paradigm for the modernization of traditional Chinese medicines(TCM) and combinatorial drugs discovery, which is an interdisciplinary science for establishing the in vitro and in vivo correlation between absorption, distribution, metabolism, and excretion/pharmacokinetic(ADME/PK) profiles of TCM and the molecular networks of disease by the integration of the knowledge of multi-disciplinary and multi-stages. In the present study, an internet-based Computation Platform for IP of TCM(TCM-IP, www.tcmip.cn) is established to promote the development of the emerging discipline. Among them, a big data of TCM is an important resource for TCM-IP including Chinese Medicine Formula Database, Chinese Medical Herbs Database, Chemical Database of Chinese Medicine, Target Database for Disease and Symptoms, et al. Meanwhile, some data mining and bioinformatics approaches are critical technology for TCM-IP including the identification of the TCM constituents, ADME prediction, target prediction for the TCM constituents, network construction and analysis, et al. Furthermore, network beautification and individuation design are employed to meet the consumer's requirement. We firmly believe that TCM-IP is a very useful tool for the identification of active constituents of TCM and their involving potential molecular mechanism for therapeutics, which would wildly applied in quality evaluation, clinical repositioning, scientific discovery based on original thinking, prescription compatibility and new drug of TCM, et al.

Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis.

We selected 42 early-stage primary biliary cirrhosis (PBC) patients and 30 healthy controls (HC). Metagenomic sequencing of the 16S rRNA gene was used to characterize the fecal microbiome. UPLC-MS/MS assaying of small molecules was used to characterize the metabolomes of the serum, urine and feces. Liquid chip assaying of serum cytokines was used to characterize the immune profiles. The gut of PBC patients were depleted of some potentially beneficial bacteria, such as Acidobacteria, Lachnobacterium sp., Bacteroides eggerthii and Ruminococcus bromii, but were enriched in some bacterial taxa containing opportunistic pathogens, such as γ-Proteobacteria, Enterobacteriaceae, Neisseriaceae, Spirochaetaceae, Veillonella, Streptococcus, Klebsiella, Actinobacillus pleuropneumoniae, Anaeroglobus geminatus, Enterobacter asburiae, Haemophilus parainfluenzae, Megasphaera micronuciformis and Paraprevotella clara. Several altered gut bacterial taxa exhibited potential interactions with PBC through their associations with altered metabolism, immunity and liver function indicators, such as those of Klebsiella with IL-2A and Neisseriaceae with urinary indoleacrylate. Many gut bacteria, such as some members of Bacteroides, were altered in their associations with the immunity and metabolism of PBC patients, although their relative abundances were unchanged. Consequently, the gut microbiome is altered and may be critical for the onset or development of PBC by interacting with metabolism and immunity.

The effects of nesfatin-1 in the paraventricular nucleus on gastric motility and its potential regulation by the lateral hypothalamic area in rats.

The current study investigated the effects of nesfatin-1 in the hypothalamic paraventricular nucleus (PVN) on gastric motility and the regulation of the lateral hypothalamic area (LHA). Using single unit recordings in the PVN, we show that nesfatin-1 inhibited the majority of the gastric distention (GD)-excitatory neurons and excited more than half of the GD-inhibitory (GD-I) neurons in the PVN, which were weakened by oxytocin receptor antagonist H4928. Gastric motility experiments showed that administration of nesfatin-1 in the PVN decreased gastric motility, which was also partly prevented by H4928. The nesfatin-1 concentration producing a half-maximal response (EC50) in the PVN was lower than the value in the dorsomedial hypothalamic nucleus, while nesfatin-1 in the reuniens thalamic nucleus had no effect on gastric motility. Retrograde tracing and immunofluorescent staining showed that nucleobindin-2/nesfatin-1 and fluorogold double-labeled neurons were observed in the LHA. Electrical LHA stimulation changed the firing rate of GD-responsive neurons in the PVN. Pre-administration of an anti- nucleobindin-2/nesfatin-1 antibody in the PVN strengthened gastric motility and decreased the discharging of the GD-I neurons induced by electrical stimulation of the LHA. These results demonstrate that nesfatin-1 in the PVN could serve as an inhibitory factor to inhibit gastric motility, which might be regulated by the LHA.

[Effect of orexin-A and orexin-1 receptor antagonist injected into the fourth ventricle of rats on food-intake and spontaneous physical activity].

The present study was aimed to investigate the effects of orexin-A and orexin-1 receptor (OX1R) antagonist injected into the fourth ventricle of rats on food-intake and spontaneous physical activity (SPA). Obese rat model was induced by high fat diet. Different doses of orexin-A or SB334867, an OX1R antagonist, were injected into the fourth ventricle of obese and normal rats respectively. SPA and food intake were monitored for 4 h after injection in both light and dark environment. In the light measurement cycle, different doses of orexin-A significantly stimulated feeding and SPA in all injected rats, and the animals' responses showed a dose-dependent manner (P < 0.05-0.01), and compared with those of normal rats, the orexin-A induced food intake and SPA were more pronounced in obese rats. In the dark measurement cycle, different doses of orexin-A had no obvious effect on food intake and SPA in both normal and obese rats (P > 0.05). In the light cycle, different doses of SB334867 significantly decreased food intake and SPA in all rats during 0-2 h and 2-4 h after injection (P < 0.05), but the food intake and SPA in obese rats were significantly greater than those of normal rats. In the dark cycle, different doses of SB334867 showed no obvious effect on food intake and SPA of normal and obese rats (P > 0.05). These results suggest that fourth cerebral ventricle nuclei may be one target for orexin-A and light condition may play an important role in orexin-A and OX1R physiological functional processes.

Xinshubao tablet rescues cognitive dysfunction in a mouse model of vascular dementia: Involvement of neurogenesis and neuroinflammation.

Vascular dementia (VaD) represents a severe cognitive dysfunction syndrome closed linked to cardiovascular function. In the present study, we assessed the potential of Xinshubao tablet (XSB), a traditional Chinese prescription widely used for cardiovascular diseases, to mitigate neuropathological damage in a mouse model of VaD and elucidated the underlying mechanisms. Our findings revealed that oral administration of XSB rescued the cardiac dysfunction resulting from bilateral common carotid artery stenosis (BCAS), improved the cerebral blood flow (CBF) and cognitive function, reduced white matter injury, inhibited excessive microglial and astrocytic activation, stimulated hippocampal neurogenesis, and reduced neural apoptosis in the brains of BCAS mice. Mechanistically, RNA-seq analysis indicated that XSB treatment was significantly associated with neuroinflammation, vasculature development, and synaptic transmission, which were further confirmed by q-PCR assays. Western blot results revealed that XSB treatment hindered the nuclear translocation of nuclear factor-κB (NF-κB), thereby suppressing the NF-κB signaling pathway. These results collectively demonstrated that XSB could ameliorate cognitive dysfunction caused by BCAS through regulating CBF, reducing white matter lesions, suppressing glial activation, promoting neurogenesis, and mitigating neuroinflammation. Notably, the NF-κB signaling pathway emerged as a pivotal player in this mechanism.

Central nesfatin-1 influences the excitability of ghrelin-responsive gastric distension neurons in the arcuate nucleus and reduces gastric motility in rats.

Although the novel satiety peptide nesfatin-1 has been shown to regulate gastric motility, the underlying mechanisms have yet to be elucidated. The study aimed to explore the effects of nesfatin-1 on ghrelin-responsive gastric distension (GD) neurons in the arcuate nucleus (Arc), and potential regulation mechanisms of gastric motility by the paraventricular nucleus (PVN). Single-unit discharges in the Arc were recorded extracellularly, and gastric motility in conscious rats was monitored during the administration of nesfatin-1 to the Arc or electrical stimulation of the PVN. Retrograde tracing and fluo-immunohistochemistry staining were used to determine NUCB2/nesfatin-1 neuronal projections. Nesfatin-1 inhibited most of the ghrelin-responsive GD-excitatory neurons, but excited ghrelin-responsive GD-inhibitory neurons in the Arc. Gastric motility was significantly reduced by nesfatin-1 administration to the Arc in a dose-dependent manner. The firing activity in the Arc and changes to gastric motility were partly reduced by SHU9119, an antagonist of melanocortin 3/4 receptors. Electrical stimulation of PVN excited most of the ghrelin-responsive GD neurons in the Arc and promoted gastric motility. Nonetheless, pretreatment with an anti-NUCB2/nesfatin-1 antibody in the Arc further increased the firing rate of most of the ghrelin-responsive GD-excitatory neurons and decreased the ghrelin-responsive GD-inhibitory neurons following electrical stimulation of the PVN. Gastric motility was enhanced by pretreatment with an anti-NUCB2/nesfatin-1 antibody in the Arc following PVN stimulation. Furthermore, NUCB2/nesfatin-1/fluorogold double-labeled neurons were detected in the PVN. These results suggest that nesfatin-1 could serve as an inhibitory factor in the Arc to regulate gastric motility via the melanocortin pathway. The PVN could be involved in the regulation of the Arc in gastric activity.