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Dissolved carbon in groundwater plays an important role in carbon cycling and ecological function maintenance, and its concentration level affects the migration and transformation of pollutants in groundwater. To understand the spatiotemporal variation characteristics of dissolved carbon and its driving factors in shallow groundwater around plateau lakes, variations in the concentrations of dissolved organic carbon （DOC）, inorganic carbon （DIC）, and total carbon （DTC） and their driving factors in shallow groundwater （ n = 404） around eight plateau lakes were analyzed. The results indicated that the average values of ρ （DOC）, ρ （DIC）, and ρ （DTC） in shallow groundwater around plateau lakes were 8.23, 49.01, and 57.84 mg·L -1 , respectively, with the ρ （DOC） in 79.0% of shallow groundwater samples exceeding 5 mg·L -1 . There were no significant differences in the DOC, DIC, and DTC concentrations between rainy and dry seasons, whereas the change in dissolved carbon concentrations in shallow groundwater were strongly affected by the intensity of agricultural intensification and the depth of groundwater table； the DOC, DIC, and DTC concentrations in shallow groundwater from facility agricultural regions （SFAR）, cropland fallow agricultural regions （CFAR）, and intensive agricultural regions with deeper groundwater tables （DIAR） were significantly reduced by 25.8% - 56.6%, 14.0% - 32.9%, and 16.6% - 36.7%, respectively, compared with those in intensive agricultural regions with shallower groundwater tables （SIAR）. Additionally, the dissolved carbon concentrations in shallow groundwater from DIAR were significantly lower than those of SFAR and CFAR. RDA revealed that physicochemical factors in water and soil significantly explained the changes in the dissolved carbon concentrations. Moreover, the dissolved carbon concentrations in shallow groundwater around Yilong Lake were significantly higher than those of other lakes, whereas that of Chenghai Lake was significantly lower than that of other lakes. Our study highlights that agricultural intensification intensity and groundwater table depth jointly drove the variations in dissolved carbon concentrations in shallow groundwater around plateau lakes. The study results are expected to provide a scientific basis for understanding the carbon cycle in plateau lake areas with underground runoff flowing into lakes and evaluating the attenuation of pollutants by dissolved carbon in shallow groundwater.

Nucleic acid modifications play important roles in biological activities and disease occurrences, and have been considered as cancer biomarkers. Due to the relatively low amount of nucleic acid modifications in biological samples, it is necessary to develop sensitive and reliable qualitative and quantitative methods to reveal the content of any modifications. In this review, the key processes affecting the qualitative and quantitative analyses are discussed, such as sample digestion, nucleoside extraction, chemical labeling, chromatographic separation, mass spectrometry detection, and data processing. The improvement of the detection sensitivity and specificity of analytical methods based on mass spectrometry makes it possible to study low-abundance modifications and their biological functions. Some typical nucleic acid modifications and their potential as biomarkers are displayed, and efforts to improve diagnostic accuracy are discussed. Future perspectives are raised for this research field.

Elucidating the main sources and transformation process of nitrate for the prevention and control of groundwater nitrogen pollution and the development and utilization of groundwater resources has great significance. To explore the current situation and source of nitrate pollution in shallow groundwater around the Dianchi Lake, 73 shallow groundwater samples were collected in the rainy season in 2020(October) and dry season in 2021(April). Using the hydrochemistry and nitrogen and oxygen isotopes( δ 15 N-NO 3 - and δ 18 O-NO 3 - ), the spatial distribution, source, and transformation process of nitrate in shallow groundwater were identified. The contribution of nitrogen from different sources to nitrate in shallow groundwater was quantitatively evaluated using the isotope mixing model(SIAR). The results showed that in nearly 40.5% of sampling points in the shallow groundwater in the dry season, ρ (NO 3 - -N) exceeded the 20 mg·L -1 specified in the Class Ⅲ water quality standard for groundwater(GB/T 14848), and in more than 47.2% of sampling points in the rainy season, ρ (NO 3 - -N) exceeded 20 mg·L -1 . The analysis results of nitrogen and oxygen isotopes and SIAR model showed that soil organic nitrogen, chemical fertilizer nitrogen, and manure and sewage nitrogen were the main sources of nitrate in shallow groundwater; these nitrogen sources contributed 13.9%, 11.8%, and 66.5% to nitrate in shallow groundwater in the dry season and 33.7%, 31.1%, and 25.9% in the rainy season, respectively. However, the contribution rate of atmospheric nitrogen deposition was only 8.5%, which contributed little to the source of nitrate in shallow groundwater in the study area. Nitrification was the leading process of nitrate transformation in shallow groundwater in the dry season, denitrification was the dominant process in the rainy season, and denitrification was more noticeable in the rainy season than that in the dry season.

The extensive application of phosphorus fertilizers to croplands and the aggregation of towns and villages around plateau lakes has resulted in the continuous accumulation of phosphorus in the soil profile and the discharge of phosphorus pollutants, which causes phosphorus pollution in shallow groundwater around the lakes. The phosphorus entering the lake with shallow underground runoff in the region around the lake also affects the water quality safety of plateau lakes. The spatiotemporal differences in phosphorus concentrations in 452 shallow groundwater samples and the driving factors were analyzed by monitoring wells in croplands and residential areas around the eight lakes in Yunnan province during the rainy and dry seasons from 2019 to 2021. The results showed that seasonal changes and land use influenced phosphorus concentrations and their composition in shallow groundwater. The concentration of phosphorus in shallow groundwater in the rainy season was higher than that in the dry season, and it was also greater in cropland than that in residential areas. DTP was the dominant form of TP, accounting for 75%-81%, and DIP was the dominant form of DTP, accounting for 74%-80%. Nearly 30% of the samples around the eight lakes had TP concentrations exceeding the surface water Class Ⅲ standard (GB 3838); the exceeded rates of phosphorus in groundwater around the Erhai Lake (52%), Qiluhu Lake (45%), Xingyun Lake (42%), and Dianchi Lake (29%) were far higher than those of Yangzonghai Lake (16%), Fuxianhu Lake (13%), Chenghai Lake (6%), and Yilonghu Lake (5%). The key driving factors of phosphorus concentrations in shallow groundwater were water-soluble phosphorus (WEP), water content (MWC), soil organic matter (SOM), total nitrogen (TN), pH in the soil profile, and pH and groundwater level in the shallow groundwater ( P <0.05). The increases in WEP, SOM, TN, and MWC in the soil and pH in groundwater significantly increased the concentrations of DIP and DTP in shallow groundwater, whereas the decrease in groundwater level significantly reduced the concentrations of DTP and DIP in the groundwater.

Shallow groundwater around plateau lakes is one of the important sources of production and potable water. Shallow groundwater NO 3 - -N pollution driven by factors such as surface nitrogen input load, rainfall, and irrigation is serious and threatens the water quality of plateau lakes. In order to identify the characteristics of nitrogen pollution and its driving factors in shallow groundwater, 463 shallow groundwater samples were collected from wells in farmland and residential areas around eight plateau lakes of Yunnan in the rainy and dry seasons in 2020 and 2021. The results showed that the average values of ρ (TN), ρ (NO 3 - -N), ρ (ON), and ρ (NH 4 + -N) in shallow groundwater were 24.35, 15.15, 8.41, and 0.79 mg·L -1 , respectively. Nearly 32% of the shallow groundwater samples around the eight lakes failed to meet the groundwater Class Ⅲ water quality requirements (GB/T 14848) of 20 mg·L -1 for NO 3 - -N. Among them, the NO 3 - -N concentration in the shallow groundwater around Erhai Lake, Qiluhu Lake, and Dianchi Lake had the highest rate of exceeding the standard, followed by that around Xingyunhu Lake, Yangzonghai Lake, Yilonghu Lake, Fuxianhu Lake, and Chenghai Lake as the smallest. Land use and seasonal changes affected the concentration and composition of various forms of nitrogen in shallow groundwater. The concentration of various forms of nitrogen in shallow groundwater in the farmland area was higher than that in the residential area. The nitrogen concentration in shallow groundwater in farmland was higher than that in residential areas. Except for NH 4 + -N, the concentration of various forms of nitrogen in shallow groundwater in the rainy season was higher than that in the dry season. NO 3 - -N was the main nitrogen form in shallow groundwater; the fraction of TN was 57%-68%, and the fraction of ON was 27%-38%. The EC, DO, ORP, and T in shallow groundwater were the key factors reflecting or affecting the concentration of various forms of nitrogen in shallow groundwater, whereas soil factors had a weak impact on the concentration of various forms of nitrogen in shallow groundwater.

Mitigating greenhouse gas emissions is necessary to reduce the overall negative climate change impacts on crop yields and agricultural production. However, certain mitigation measures may generate unintended consequences to food availability and food access due to both land use competition and economic burden of mitigation. Integrated assessment models (IAM) are generally used to evaluate these policies; however, currently these models may not capture the importance of income and food prices for hunger and overall economic wellbeing. Here, we implement a measure of food security that captures the nutritional and economic aspects as the total expenditures on staple foods divided by income and weighted by total caloric consumption in an IAM, the global change analysis model (GCAM4.0). We then project consumer prices and our measure of food security along the shared socioeconomic pathways. Sustained economic growth underpins increases in caloric consumption and lowering expenditures on staple foods. Strict conservation policies affect food accessibility in a larger number of developing countries, whereas the negative effects of pricing terrestrial emissions are more concentrated on the poor in Sub-Saharan Africa, by substantially replacing their cropland with forests and affecting the production of key staples., Supplementary Information: The online version contains supplementary material available at 10.1007/s10669-022-09860-4., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Crown 2022.)

Clean air policies in China have substantially reduced particulate matter (PM 2.5 ) air pollution in recent years, primarily by curbing end-of-pipe emissions. However, reaching the level of the World Health Organization (WHO) guidelines may instead depend upon the air quality co-benefits of ambitious climate action. Here, we assess pathways of Chinese PM 2.5 air quality from 2015 to 2060 under a combination of scenarios that link global and Chinese climate mitigation pathways (i.e. global 2°C- and 1.5°C-pathways, National Determined Contributions (NDC) pledges and carbon neutrality goals) to local clean air policies. We find that China can achieve both its near-term climate goals (peak emissions) and PM 2.5 air quality annual standard (35 μg/m 3 ) by 2030 by fulfilling its NDC pledges and continuing air pollution control policies. However, the benefits of end-of-pipe control reductions are mostly exhausted by 2030, and reducing PM 2.5 exposure of the majority of the Chinese population to below 10 μg/m 3 by 2060 will likely require more ambitious climate mitigation efforts such as China's carbon neutrality goals and global 1.5°C-pathways. Our results thus highlight that China's carbon neutrality goals will play a critical role in reducing air pollution exposure to the level of the WHO guidelines and protecting public health., (© The Author(s) 2021. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.)

More than half of current coal power capacity is in China. A key strategy for meeting China's 2060 carbon neutrality goal and the global 1.5 °C climate goal is to rapidly shift away from unabated coal use. Here we detail how to structure a high-ambition coal phaseout in China while balancing multiple national needs. We evaluate the 1037 currently operating coal plants based on comprehensive technical, economic and environmental criteria and develop a metric for prioritizing plants for early retirement. We find that 18% of plants consistently score poorly across all three criteria and are thus low-hanging fruits for rapid retirement. We develop plant-by-plant phaseout strategies for each province by combining our retirement algorithm with an integrated assessment model. With rapid retirement of the low-hanging fruits, other existing plants can operate with a 20- or 30-year minimum lifetime and gradually reduced utilization to achieve the 1.5 °C or well-below 2 °C climate goals, respectively, with complete phaseout by 2045 and 2055.

A rapid transition away from unabated coal use is essential to fulfilling the Paris climate goals. However, many countries are actively building and operating coal power plants. Here we use plant-level data to specify alternative trajectories for coal technologies in an integrated assessment model. We then quantify cost-effective retirement pathways for global and country-level coal fleets to limit long-term temperature change. We present our results using a decision-relevant metric: the operational lifetime limit. Even if no new plants are built, the lifetimes of existing units are reduced to approximately 35 years in a well-below 2 °C scenario or 20 years in a 1.5 °C scenario. The risk of continued coal expansion, including the near-term growth permitted in some Nationally Determined Contributions (NDCs), is large. The lifetime limits for both 2 °C and 1.5 °C are reduced by 5 years if plants under construction come online and 10 years if all proposed projects are built.

The objective of this paper was to evaluate the effect of vanadium (V) in high-fat diets sourced from egg yolk on body weight gain, feed intake, blood characteristics and antioxidative status of Wistar rats. A total of 72 female Wistar rats were allocated according to a 2 × 4 factorial design throughout a 5-wk trial, including 2 levels of dietary fat (normal and high; ether extract 40.3 and 301.2 g/kg; fat sourced from egg yolk) and 4 levels of dietary V (0, 3, 15 and 30 mg/kg). Vanadium decreased ( P  ≤ 0.05) body weight gain (V at 30mg/kg during wk 1 and 2; V at 15 and 30 mg/kg during the overall phase), feed intake (V at 30 mg/kg during wk 3 and the overall phase; V at 15 and 30 mg/kg during wk 4), but increased the relative weight of liver (V at 30 mg/kg, P  ≤ 0.05). Moreover, increasing dietary V significantly increased ( P  ≤ 0.05) plasma aspartate aminotransferase, alanine aminotransferase and malondialdehyde levels and decreased triglyceride level, and V at 30 mg/kg in high-fat treatment had the highest or lowest values (interaction, P  ≤ 0.05). Under the same dietary V dose, V residual content in liver (dietary V at 15 and 30 mg/kg) and kidney (dietary V at 15 mg/kg) was higher in high-fat diet treatment compared with normal-fat diet treatment ( P  ≤ 0.05). In conclusion, it is suggested that V could decrease the body weight together with the feed intake, and the high fat could enhance oxidative stress induced by V of Wistar rats.

Integrative pharmacology (IP) is a discipline that studies the interaction, integration and principle of action of multiple components with the body, emphasizing the integrations of multi-level and multi-link, such as "whole and part", " in vivo and in vitro ", " in vivo process and activity evaluation". After four years of development and practice, the theory and method of IP has received extensive attention and application.In order to better promote the development of IP, this paper systematically reviews the concepts, research contents, research methods and application fields about IP., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

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., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

The study was conducted to assess the effect of vanadium (V) in high-fat diet on the liver and kidney of rats in a 5-week trial. Seventy-two female Wistar rats (BW = 95 ± 5 g) were randomly allotted into eight groups. Groups I, II, III, and IV obtained low-fat diet containing 0, 3, 15, and 30 mg/kg V, and V, VI, VII, and VIII groups received the respective vanadium doses with high-fat diet, respectively. There were lesions in the liver and kidney of V, VI, VII, and VIII groups, granular degeneration and vacuolar degeneration were observed in the renal tubular and glomerulus epithelial cells, and hepatocytes showed granular degeneration and vacuolar degeneration. Supplemented high-fat diet with vanadium was shown to decrease (P < 0.05) activities of superoxide dismutase, total antioxidant capacity, glutathione-S transferase, and NAD(P)H/quinone oxidoreductase 1 (NQO1) and increase malondialdehyde content in the liver and kidney. The relative expression of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and NQO1 mRNA was downregulated by V addition and high-fat diet, and the effect of V was more pronounced in high-fat diet (interaction, P < 0.05), with VIII group having the lowest mRNA expression of Nrf-2 and NQO1 in the liver and kidney. In conclusion, it suggested that dietary vanadium ranging from 15 to 30 mg/kg could lead to oxidative damage and vanadium accumulation in the liver and kidney, which caused renal and hepatic toxicity. The high-fat diet enhanced vanadium-induced hepatic and renal damage, and the mechanism was related to the modulation of the hepatic and renal mRNA expression of Nrf-2 and NQO1.

Research on the interaction between dietary vitamins and intestinal bacteria is poorly understood. To investigate the effect of dietary vitamins on the cecal bacterial communities, 2 bacterial 16S rRNA gene clone libraries were constructed from pooled PCR products obtained from the cecal digesta of 28-d broilers fed diets with vitamins (V) at the NRC level or with no vitamins (NV). The results showed that BW gain and average feed intake of V broilers was significantly higher (P < 0.01) than NV broilers, whereas the feed/gain ratio was significantly lower (P < 0.01) in V broilers. A total of 188 and 185 clones were sequenced for the NV and V broilers, respectively. Sequence identity criterion of 98% was used to assign sequences to operational taxonomic units (OTU). Clones from the NV group broilers were assigned to 14 OTU, with 33% clones affiliated with the genus Clostridium, 19% affiliated with the genera Escherichia/Shigella, 14% affiliated with the genus Bacteroides, and the remaining clones (34%) affiliated with 5 other bacterial genera (Faecalibacterium, Parasporobacterium, Ruminococcus, Streptococcus, and Subdoligranulum). Clones from the V group broilers were assigned to 23 OTU, with 46% of the clones affiliated with the genus Clostridium, 11% affiliated with the genus Fecalibacterium, and the remaining clones (43%) affiliated with 8 other genera (Anaerofilum, Lactobacillus, Anaerotruncus, Oscillibacter, Alistipes, Gracilibacter, Acetivibrio, and Haloplasma). Three OTU assigned to Clostridium, Faecalibacterium, and Ruminoccus were shared between the 2 libraries. Shannon diversity index showed the V broilers exhibited significantly higher bacterial diversity (P = 0.05), and Libshuff analysis indicated that the community structure between the 2 groups was significantly different (P < 0.0001). These results suggest that lack of dietary vitamins can increase the ratio of facultative pathogenic bacteria and decrease the diversity of bacteria in the cecum of broilers. Our results provide new leads for further investigations on the interaction between dietary vitamin additives and the gut health of broilers.

Dielectric properties of poly(vinylidene fluoride) (PVDF) based nanocomposites filled with surface hydroxylated BaTiO(3) (h-BT) nanoparticles were reported. The h-BT fillers were prepared from crude BaTiO(3) (c-BT) in aqueous solution of H(2)O(2). Results showed that the dielectric properties of the h-BT/PVDF nanocomposites had weaker temperature and frequency dependences than that of c-BT/PVDF nanocomposites. Meanwhile, the h-BT/PVDF composites showed lower loss tangent and higher dielectric strength. It is suggested that the strong interaction between h-BT fillers and PVDF matrix is the main reason for the improved dielectric properties.

Polypeptide from Chlamys farreri (PCF) has been identified as a potent antioxidant and photoprotective agent. In this study, we investigated whether PCF could inhibit apoptosis of murine thymocytes induced by ultraviolet B (UVB) and modulate UVB induced the mitogen-activated protein kinases (MAPKs) cascade in vitro. Our results show that PCF inhibit UVB-induced apoptotic cell death in murine thymocytes. We also found that PCF potently stimulated the phosphorylation of ERKs, which is involved in the cell survival-signaling cascade. Furthermore, the specific inhibition of the ERKs pathways by PD98059 reduced the cytoprotective effect of PCF. On the other hand, the JNKs and p38 inhibitor SP600125 and SB203580 additively enhanced the cytoprotective effect of PCF. We concluded that the activation of JNKs and p38 kinase played an important role in UVB-induced apoptosis, and PCF likely exerted its cytoprotective effect in thymocytes through ERKs activation. These suggested that part of the antiapoptotic effect of PCF might be mediated by its ability to modulate the MAPKs cascade.

Traditionally, steroid hormone effects have been described as a result of the modulation of nuclear transcription, thus triggering genomic events that are responsible for physiological effects. Despite early observations of rapid steroid effects that were incompatible with this theory, nongenomic steroid effects have been widely recognized only recently. However, the nongenomic effect of glucocorticoid (GC) on anti-inflammation and immunosuppression has not been reported. Macrophages play important roles in inflammation and the immune response. The present experiment selected macrophages as experimental cells to explore the nongenomic effects and possible mechanisms of GCs on phagocytosis and superoxide anion production. Phagocytosis by macrophages was detected by the neutral red uptake assay. The superoxide anions were measured by cytochrome C reduction assay. It was found that both 10(-4) and 10(-5) mol/L corticosterone (CORT) rapidly inhibited uptake of neutral red by macrophages in less than 30 min, and the inhibition by the former was stronger than that of the latter. CORT (10(-4) to 10(-10) mol/L) rapidly inhibited superoxide anion production by macrophages in less than 30 min. The above-mentioned effects were insensitive to the GC-receptor antagonist mifepristone (RU486) and the translation inhibitor actidione. CORT coupled to bovine serum albumin (BSA-CORT) was able to mimic the rapid inhibitory effects of CORT. The results indicated that CORT could rapidly inhibit phagocytosis and superoxide anion production by mouse peritoneal macrophages in vitro in less than 30 min by a rapid, nongenomic mechanism, which contributes to the anti-inflammatory and immunosuppressive actions of GCs. These data shed a new light on the clinical application of GCs.

We have previously reported that polypeptide from Chlamys farreri (PCF) inhibits the oxidative damage of ultraviolet A (UVA) on HeLa cells in vitro [Acta Pharm. Sin. 23 (2002) 961]. To further elucidate a possible role for PCF on UVA-damaged normal human cells, we established the oxidative damage models of normal human dermal fibroblasts (NHDF) exposed to UVA to study the protective effect of PCF on human dermal fibroblasts in vitro. In this study, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method was used to detect the cell viability. The intracellular superoxide dismutase (SOD), glutathione peroxidase (GSH-px), catalase (CAT), xanthine oxidase (XOD), malondialdehyde (MDA), reactive oxygen species (ROS), total antioxidative capacity (T-AOC), and anti-superoxide anion capacity (A-ASC) were measured. The effect of PCF on UVA-induced apoptosis were investigated by Annexin V-FITC assay. Intracellular calcium was determined with the calcium-sensitive fluorochrome Fluo-3, and mitochondrial transmembrane potential with rhodamine 123. Comet assay was employed to detect the UVA-induced DNA damage. The ultrastructure of cell was observed under transmission electron microscope. The results indicated that PCF could greatly enhance the viability of NHDF and markedly promote SOD, GSH-px, T-AOC, and A-ASC, while the amounts of MDA and ROS, the activity of XOD were decreased. PCF could inhibit UVA-induced apoptosis and DNA damage in NHDF. The concentration of cellular free calcium was decreased and the mitochondrial transmembrane potential was increased by PCF. In ultrastructure of NHDF, PCF could greatly decrease UVA-induced damage, especially membrane. Our results suggest that the supplementation of PCF appears to reduce the UVA-induced normal human dermal fibroblasts damage efficiently. It may be involved in the PCF's abilities of scavenging oxygen free radical, inhibiting lipid peroxidation, increasing antioxidative enzymes, decreasing intracellular calcium and protection of membrane structure in NHDF irradiated by UVA.

Recent work shows that the intracellular free Ca2+ concentrations ([Ca2+]i) of the presynaptic and postsynaptic neurons play crucial signaling roles in short- and long-term synaptic plasticity. Residual [Ca2+]i followed conditioning stimulation may cause short-term synaptic enhancement. Presynaptic [Ca2+]i could influence the replacing of presynaptic depressed vesicles, as well as encode the precise relative timing of presynaptic input and postsynaptic activity and generate long-term synaptic modification of opposite polarity(LTP or LTD).

Interferon-alpha (IFNalpha) is not only an immunoregulatory factor, but is also an analgesic molecule. The analgesic effect of IFNalpha was mediated by mu opioid receptor. After the 129th Tyr residue of human IFNalpha was mutated to Ser, the antiviral activity almost disappeared, but there still remained a strong analgesic activity that could be blocked by naloxone. These results indicate that there exist distinct domains in the IFNalpha molecule, which mediate immune and analgesic effects respectively, and suggest that there are different receptor mechanisms inducing immune and analgesic effects of IFNalpha. However, although the antiviral activity of IFNalpha decreased to 34.1% of wild type IFNalpha after the 122nd Tyr residue was changed to Ser, the analgesic activity of this mutant was lost completely. There were significant cross reactivities between INFalpha and anti-opioid sera. These studies show strong structural and functional similarities between INFalpha and opioid peptides, and inferred that the analgesic domain locates around the 122nd Tyr residue of IFNalpha molecule in tertiary structure.

Using the tail-flick induced by electro-stimulation as a pain marker, it was found that pain threshold (PT) was significantly increased after injecting interferon-alpha (IFN alpha) into the lateral ventricle of rats. This effect was dosage-dependent and abolished by monoclonal antibody (McAb) to IFN alpha. Naloxone could inhibit the analgesic effect of IFN alpha, suggesting that the analgesic effect of IFN alpha be related to the opioid receptors. Beta-funaltrexamine (beta-FNA), the mu specific receptor antagonist could completely block the analgesic effect of IFN alpha. The selective delta-opioid receptor antagonist, ICI174,864 and the kappa-opioid receptor antagonist, nor-BNI both failed to prevent the analgesic effect of IFN alpha. IFN alpha could significantly inhibit the production of the cAMP stimulated by forskolin in SK-N-SH cells expressing the mu-opioid receptor, not in NG108-15 cells expressing the delta-opioid receptor uniformly. The results obtained provide further evidence for opioid activity of IFN alpha and suggest that this effect is mediated by central opioid receptors of the mu subtype. The evidence is consistent with the hypothesis that multiple actions of cytokines, such as immunoregulatory and neuroregulatory effects, might be mediated by distinct domains of cytokines interacting with different receptors.