Frontiers and future perspectives of neuroimmunology.

Neuroimmunology is an interdisciplinary branch of biomedical science that emerges from the intersection of studies on the nervous system and the immune system. The complex interplay between the two systems has long been recognized. Research efforts directed at the underlying functional interface and associated pathophysiology, however, have garnered attention only in recent decades. In this narrative review, we highlight significant advances in research on neuroimmune interplay and modulation. A particular focus is on early- and middle-career neuroimmunologists in China and their achievements in frontier areas of "neuroimmune interface", "neuro-endocrine-immune network and modulation", "neuroimmune interactions in diseases", "meningeal lymphatic and glymphatic systems in health and disease", and "tools and methodologies in neuroimmunology research". Key scientific questions and future directions for potential breakthroughs in neuroimmunology research are proposed.

Effects of raw and wine-processed Schisandra chinensis on neuro-endocrine-immune network in insomnia mice and its mechanism / 中国药房

OBJECTIVE To investigate the effect of raw and wine-processed Schisandra chinensis on neuro-immune-endocrine network in insomnia mice and its mechanism. METHODS Fifty mice were randomly divided into blank group， model group， diazepam group， raw S. chinensis group and wine-processed S. chinensis group， with 10 mice in each group. Except for blank group， the mice in the other groups were intraperitoneally injected with thyroxine solution to establish mice model of insomnia； at the end of each day’s modeling， the corresponding doses of diazepam，raw and wine-processed S. chinensis were given by gavage. The blank group and model group were given constant volume of normal saline. The general state of the mice was observed and recorded， and the total activity distance and upright times of the mice were detected； the EEG and EMG signals of mice were recorded， and the time ratio of sleep wake time （wake）， non-rapid eye movement （NREM） and rapid eye movement （REM） was analyzed； the contents of neurotransmitters [γ-aminobutyric acid （GABA）， 5-hydroxytryptamine （5-HT）， dopamine （DA）， norepinephrine （NE）， cortisol （CORT）] in brain suprachiasmatic nucleus （SCN） were detected； and the expressions of tumor necrosis factor α （TNF-α） and interleukin 1β （IL-1β） were detected； the mRNA expressions of clock gene Bmal1， circadian clock gene Clock and cycle gene Per2 were all detected. RESULTS Compared with the blank group， the mental state of the model group mice was relatively depressed， the amount of food and water increased， the body mass decreased， the hair was rough and shiny， and the circadian rhythm was irregular； the total activity distance and upright times decreased significantly； the time ratio of wake increased significantly， while the time ratios of REM and NREM decreased significantly； the content of 5- HT in brain SCN decreased significantly， while the content of NE， DA and CORT increased significantly； the fluorescence intensity of IL-1β and TNF-α was significantly increased； the relative expression level of Bmal1 and Clock mRNA was significantly increased， while the relative expression level of Per2 mRNA was significantly decreased （P＜0.05 or P＜0.01）. Compared with the model group， the general state of mice in diazepam group， raw S. chinensis group and wine-processed S. chinensis group was improved obviously， and most of the above index levels were significantly reversed （P＜0.05 or P＜0.01）. CONCLUSIONS Raw and wine-processed S. chinensis have a certain therapeutic effect on insomnia mice， the mechanism of which may be related to the regulation of neuro-endocrine-immune system related biological indicators in insomnia mice.

Research Progress on the Mechanism of the Acupuncture Regulating Neuro-Endocrine-Immune Network System.

As one of the conventional treatment methods, acupuncture is an indispensable component of Traditional Chinese Medicine. Currently, acupuncture has been partly accepted throughout the world, but the mechanism of acupuncture is still unclear. Since the theory of the neuro-endocrine-immune network was put forward, new insights have been brought into the understanding of the mechanism of acupuncture. Studies have proven that acupuncture is a mechanical stimulus that can activate local cell functions and neuroreceptors. It also regulates the release of related biomolecules (peptide hormones, lipid hormones, neuromodulators and neurotransmitters, and other small and large biomolecules) in the microenvironment, where they can affect each other and further activate the neuroendocrine-immune network to achieve holistic regulation. Recently, growing efforts have been made in the research on the mechanism of acupuncture. Some researchers have transitioned from studying the mechanism of acupuncture as a single linear pathway to using systems approaches, including metabolomics, genomics, proteomics and biological pathway analysis. This review summarizes the research progress on the neuro-endocrine-immune network related mechanism of acupuncture and discusses its current challenges and future directions.

Current Tracking on Effectiveness and Mechanisms of Acupuncture Therapy: A Literature Review of High-Quality Studies.

The scientific evidence of acupuncture studies has been improved in recent years, and one of the important manifestations is that more and more acupuncture clinical trials and mechanism researches have been published in the source periodicals of Science Citation Index (SCI). This study summarized the dominant diseases of acupuncture focusing on of acupuncture efficacy and mechanisms, and discussed the existing problems, highlighting the direction of future developments. Most clinical studies were published in journals with journal impact factor (JIF) score of 10 or above, and majority of the basic researches had JIF scores of 5 to 10. The above literature were further divided according to the International Classification of Diseases (ICD). The most concerned diseases in these articles were neurological diseases, musculoskeletal system and connective tissue diseases, tumor and digestive system diseases. The therapeutic effect and mechanism of acupuncture on each kind of disease were summarized. The results showed that the therapeutic effect of acupuncture on nerve injury focused on the anti-oxidation pathway, neuroprotective and anti-inflammatory processes. The antiinflammatory effect also played an important role in the treatment of musculoskeletal diseases. The analgesic effect was underlined in most of these studies. Clinical trials were well carried out on acupuncture curative effect of tumor complications and side effects of chemo-radiotherapy, but the potential mechanisms have not been clarified. Somato-visceral reflex was suggested to be strongly associated with the effects of acupuncture changing the motor activity of the gastrointestinal tract. Functional magnetic resonance imaging studies indicated that non-specific effects play important roles in acupuncture analgesia. Lines of evidence have pointed out that the regulation of neuro-endocrine-immune networks may be a common switch of acupuncture on different nerve system diseases.

[Herbal-cake-partitioned moxibustion of "Shenque" (CV8) has a relative specific effect in relieving abdominal pain and in regulating neuroendocrine-immune network in primary dysmenorrhea rats].

OBJECTIVE: To observe the effect of herbal-cake-partitioned moxibustion (HCPM) of "Shenque" (CV8) and "Daheng" (SP15) on abdominal pain, plasma ß-endorphin (ß-EP), uterine prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) levels, as well as splenetic natural killer cell (NK cell) activity in primary dysmenorrhea (PD) rats, so as to explore the specificity of acupoint function and the underlying mechanisms of moxibustion in relieving dysmenorrhea. METHODS: A total of 40 female rats were randomized into blank control, model, CV8-direct moxibustion, CV8-HCPM and SP15-HCPM groups (n＝8 rats in each). The PD model was established by subcutaneous injection of estradiol benzoate injection (0.2-0.5 mg/rat) for 10 consecutive days and intraperitoneal injection of oxytocin (2 U) 24 h after the last subcutaneous injection. Moxibustion or herbal-cake (composed of Radix Angelicae Sinensis, Rhizoma Chuanxiong, Radix Paeoniae Rubra, Cortex Cinnamomi, etc.)-partitioned moxibustion was applied to CV8, SP15 or umbilicus respectively for 7 moxa-cones every time, once daily for 10 successive days. The rats of the control and model groups were also restrained as those in the moxibustion groups. The writhing times within 30 minutes was recorded and the contents of plasma ß-EP, uterine PGE2 and PGF2α were detected by ELISA, and NK cell activity was detected using MTT. RESULTS: Compared with the control group, the writhing times and the content of PGF2α in the uterus tissue were significantly increased in the model group (P<0.01), while the contents of plasma ß-EP, uterine PGE2 and splenetic NK cell activity were significantly decreased (P<0.01). In comparison with the model group, the writhing times and uterine PGF2α content were obviously down-regulated in the SP15-HCPM, CV8-direct moxibustion and CV8-HCPM groups (P<0.05, P<0.01), and the contents of plasma ß-EP and uterine PGE2, and splenetic NK cell activity were significantly increased (P<0.05, P<0.01). The therapeutic effects of CV8-HCPM group were significantly superior to those of SP15-HCPM and CV8-direct moxibustion groups in lowering writhing times and PGF2α level, and in up-regulating ß-EP, PGE2 (P<0.05, P<0.01). The NK cell activity of CV8-HCPM group was significantly increased compared with that in the SP15-HCPM group(P<0.05). No significant differences were found between the SP15-HCPM and CV8-direct moxibustion groups in the levels of writhing times, plasma ß-EP and uterine PGE2, PGF2α contents and splenetic NK cell activity (P>0.05). CONCLUSION: Moxibustion of both CV8 and SP15 can relieve abdominal pain in PD rats, which may be closely associated with its effect in suppressing PD-induced decrease of plasma ß-EP and uterine PGE2 levels and splenetic NK cell activity and increase of uterine PGF2α. The therapeutic effect of CV8-HCPM is obviously better than that of SP15-HCPM and CV8-direct moxibustion.

Herbal-cake-partitioned moxibustion of "Shenque" (CV8) has a relative specific effect in relieving abdominal pain and in regulating neuroendocrine-immune network in primary dysmenorrhea rats / 针刺研究

OBJECTIVE: To observe the effect of herbal-cake-partitioned moxibustion (HCPM) of "Shenque" (CV8) and "Daheng" (SP15) on abdominal pain, plasma β-endorphin (β-EP), uterine prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) levels, as well as splenetic natural killer cell (NK cell) activity in primary dysmenorrhea (PD) rats, so as to explore the specificity of acupoint function and the underlying mechanisms of moxibustion in relieving dysmenorrhea. METHODS: A total of 40 female rats were randomized into blank control, model, CV8-direct moxibustion, CV8-HCPM and SP15-HCPM groups (n＝8 rats in each). The PD model was established by subcutaneous injection of estradiol benzoate injection (0.2-0.5 mg/rat) for 10 consecutive days and intraperitoneal injection of oxytocin (2 U) 24 h after the last subcutaneous injection. Moxibustion or herbal-cake (composed of Radix Angelicae Sinensis, Rhizoma Chuanxiong, Radix Paeoniae Rubra, Cortex Cinnamomi, etc.)-partitioned moxibustion was applied to CV8, SP15 or umbilicus respectively for 7 moxa-cones every time, once daily for 10 successive days. The rats of the control and model groups were also restrained as those in the moxibustion groups. The writhing times within 30 minutes was recorded and the contents of plasma β-EP, uterine PGE2 and PGF2α were detected by ELISA, and NK cell activity was detected using MTT. RESULTS: Compared with the control group, the writhing times and the content of PGF2α in the uterus tissue were significantly increased in the model group (P0.05). CONCLUSION: Moxibustion of both CV8 and SP15 can relieve abdominal pain in PD rats, which may be closely associated with its effect in suppressing PD-induced decrease of plasma β-EP and uterine PGE2 levels and splenetic NK cell activity and increase of uterine PGF2α. The therapeutic effect of CV8-HCPM is obviously better than that of SP15-HCPM and CV8-direct moxibustion.

[Effects of the Acupoint Catgut Embedding on Nerve-Endocrine-Immune Network in Dysmenorrhea Rats].

OBJECTIVE: To explore the underlying mechanism of acupoint catgut embedding in improving primary dysme-norrhea (PD) in rats based on functional activities of the neuro-endocrine-immune (NEI) network. METHODS: Forty female rats were equally randomized into blank control, PD model, medication, and acupoint catgut embedding groups. The PD model was established by subcutaneous injection of estradiol benzoate (0.5 mg/rat on the 1st and 10th d, and 0.2 mg/rat from 2nd to 9th d) and oxytocin (2 U/rat, i．p.). Rats of the medication group were treated by intragastric perfusion of fenbid (0.8 mL/rat, 125 mg/100 mL), once daily for 10 days. The catgut embedding was applied to bilateral "Ciliao" (BL 32), "Sanyinjiao" (SP 6) and "Guanyuan" (CV 4) before modeling. The body writhing times in 30 minutes were recorded, plasma ß-endorphin(ß-EP) content, and prostaglandin E 2 (PGE2) and prostaglandin F 2 α (PGF2α) contents in the uterus tissue were assayed using ELISA, and the activity of natural killer cell (NK cell) in the spleen tissue was detected using 3-(4，5-dimethyl-2-thiazolyl)-2，5-diphenyl-2-H-tetrazolium bromide (MTT) method after isolation and co-culture with K 562 cells. RESULTS: The body writhing times were no-tably more in the model group than in the control group (P<0.01), and obviously fewer in both medication and catgut embedding groups than in the model group (P<0.01). After modeling, the plasma ß-EP and uterus PGE2 contents and splenic NK cell activity were significantly decreased (P<0.01), while the uterus PGF2α content was evidently increased in the model group relevant to the control group (P<0.01). Following the treatment, plasma ß-EP and uterus PGE2 contents and splenic NK cell activity were considerably up-regulated (P<0.01), and uterus PGF2α content was markedly down-regulated in both medication and acupoint catgut embedding groups (P<0.01), suggesting an involvement of the NEI network in catgut embedding-induced improvement of PD. The therapeutic effect of catgut embedment was markedly superior to that of medication in up-regulating splenic NK cell activity (P<0.01). No significant differences were found between the medication and catgut embedding groups in the body writhing times within 30 min, and in the levels of plasma ß-EP and uterus PGE2 and PGF2α (P>0.05). CONCLUSION: The acupoint catgut embedding has a significant efficacy in relieving PD in rats, which may be related to its effect in up-regulating plasma ß-EP, uterus PGE2 contents and splenic NK cell activity and in down-regulating uterus PGF2α level.

Effects of the Acupoint Catgut Embedding on Nerve-Endocrine-Immune Network in Dysmenorrhea Rats / 针刺研究

OBJECTIVE: To explore the underlying mechanism of acupoint catgut embedding in improving primary dysme-norrhea (PD) in rats based on functional activities of the neuro-endocrine-immune (NEI) network. METHODS: Forty female rats were equally randomized into blank control, PD model, medication, and acupoint catgut embedding groups. The PD model was established by subcutaneous injection of estradiol benzoate (0.5 mg/rat on the 1st and 10th d, and 0.2 mg/rat from 2nd to 9th d) and oxytocin (2 U/rat, i．p.). Rats of the medication group were treated by intragastric perfusion of fenbid (0.8 mL/rat, 125 mg/100 mL), once daily for 10 days. The catgut embedding was applied to bilateral "Ciliao" (BL 32), "Sanyinjiao" (SP 6) and "Guanyuan" (CV 4) before modeling. The body writhing times in 30 minutes were recorded, plasma β-endorphin(β-EP) content, and prostaglandin E 2 (PGE2) and prostaglandin F 2 α (PGF2α) contents in the uterus tissue were assayed using ELISA, and the activity of natural killer cell (NK cell) in the spleen tissue was detected using 3-(4，5-dimethyl-2-thiazolyl)-2，5-diphenyl-2-H-tetrazolium bromide (MTT) method after isolation and co-culture with K 562 cells. RESULTS: The body writhing times were no-tably more in the model group than in the control group (P0.05). CONCLUSION: The acupoint catgut embedding has a significant efficacy in relieving PD in rats, which may be related to its effect in up-regulating plasma β-EP, uterus PGE2 contents and splenic NK cell activity and in down-regulating uterus PGF2α level.

Correlation Research on the Essence of Viscera-state and Neuro-Endocrine-Immune Network-related Indicators / 中国中医药信息杂志

Objective To explore the intrinsic link between neuro-endocrine-immune (NEI) network and the viscera-state.Methods Using three databases namely TCM database, Chinese pharmacy database and combination of TCM and WM database in China Academic Journals Database, the authors searched and collected NEI-related indicators published on journals for the viscera-state researches. Then a related database was established for data mining. Through analysis of association rules, analysis of the relationship among diseases, syndromes, therapeutic principles, combination of disease and syndrome, and NEI network related indicators were performed for association rules and directional network diagrams.Results Through the association analysis, the authors drew 44 directional network diagrams of high-frequency disease positions, syndromes, therapeutic principles and NEI network related indicators, and obtained 19 association rules. Kidney and liver essence research focused on HPG axis, HPA axis, and HPT axis. Spleen essence research focused on brain-gut peptide related indicators. Heart essence research focused on vascular endothelium function indicators. Pulmonary essence research focused on humeral immunity, ET and TNF-α.Conclusion It was feasible to explore the intrinsic link between NEI network and the viscera-state by using data mining. Differences among study on NEI network of five-organs systems were found, which is of great significance for researches on the essence of the viscera-state.