Astrocytes in the spinal dorsal horn (SDH) exhibit diverse reactive phenotypes under neuropathic conditions, yet the mechanisms driving this diversity and its implications in chronic pain remain unclear. Here, we report that spared nerve injury (SNI) induces marked upregulation of both complement component 3 (C3⁺, A1-like) and S100 calcium-binding protein A10 (S100A10⁺, A2-like) astrocyte subpopulations in the SDH, with elevated microglial cytokines including interleukin-1α, tumor necrosis factor-α, and complement component 1q. Transcriptomic, immunohistochemical, and Western blot analyses reveal co-activation of multiple reactive astrocyte states over a unidirectional shift toward an A1-like phenotype. Fibroblast growth factor 8 (FGF8), a neuroprotective factor via FGFR3, mitigated microglia-induced C3⁺ astrocyte reactivity in vitro and suppressed spinal C3 expression and mechanical allodynia following intrathecal administration in SNI mice. These findings reveal a microglia-astrocyte signaling axis that promotes A1 reactivity and position FGF8 as a promising therapeutic candidate for neuropathic pain by modulating astrocyte heterogeneity.
Animals ; Astrocytes/drug effects* ; Neuralgia/pathology* ; Receptor, Fibroblast Growth Factor, Type 3/metabolism* ; Signal Transduction/physiology* ; Male ; Mice ; Microglia/drug effects* ; Fibroblast Growth Factor 8/pharmacology* ; Mice, Inbred C57BL ; Hyperalgesia/drug therapy* ; Spinal Cord/drug effects* ; Complement C3/metabolism* ; Spinal Cord Dorsal Horn/metabolism*

Sensory conflict impacts postural control, yet its effect on cortico-muscular interaction remains underexplored. We aimed to investigate sensory conflict's influence on the cortico-muscular network and postural stability. We used a rotating platform and virtual reality to present subjects with congruent and incongruent sensory input, recorded EEG (electroencephalogram) and EMG (electromyogram) data, and constructed a directed connectivity network. The results suggest that, compared to sensory congruence, during sensory conflict: (1) connectivity among the sensorimotor, visual, and posterior parietal cortex generally decreases, (2) cortical control over the muscles is weakened, (3) feedback from muscles to the cortex is strengthened, and (4) the range of body sway increases and its complexity decreases. These results underline the intricate effects of sensory conflict on cortico-muscular networks. During the sensory conflict, the brain adaptively decreases the integration of conflicting information. Without this integrated information, cortical control over muscles may be lessened, whereas the muscle feedback may be enhanced in compensation.
Humans ; Muscle, Skeletal ; Electromyography/methods* ; Electroencephalography/methods* ; Brain ; Brain Mapping

Objective To investigate the effects of long-term administration of tacrolimus(also known as FK506)on the pain-related behaviors in mice and to study the underlying mechanism of pain induced by FK506 via measuring the effect of FK506 on the synaptic expression and phosphorylation of alpha-amino-3-hyroxy-5-methyl-4-isoxazolepropionic acid(AMPA)receptor in the spinal cord dorsal horn of mice.Methods 1)A total of 24 mice were evenly and randomly assigned to two groups,a FK506 group and a Saline group.The FK506 group was given daily intraperitoneal injection of FK506 and the Saline group received normal saline.Both groups received injection once a day for 7 days in a row.Some of the mice(n=6 in each group)were monitored for the changes in the paw withdrawal threshold(PWT),the paw withdrawal latency(PWL),and the spontaneous pain behaviors to establish the pain model.The other mice(n=6 in each group)of each group underwent isolation of the dorsal horn when obvious pain symptoms were induced on day 7 of injection.Then,immunoblotting was performed to determine the synaptic expression and phosphorylation levels of GluA1 and GluA2 subunits of AMPA receptors.2)The mice were randomly divided into two groups,FK506+calcineurin(CaN)group and FK506+Saline group(n=6 in each group).After the pain model was constructed,the mice were given intrathecal injection of recombinant CaN(also know as 33 U)or normal saline.Then,60 minutes later,the PWT and the PWL of the mice were measured to investigate the role of CaN in FK506-induced pain.3)Another18 mice were selected.The mice were randomly and evenly assigned to three groups,a control group(receiving intraperitoneal injection of normal saline followed by intrathecal injection of normal saline),FK506+Saline group(receiving intraperitoneal injection of FK506 followed by intrathecal injection of normal saline)and FK506+CaN group(receiving intraperitoneal injection of FK506 followed by intrathecal injection of CaN).Then,60 minutes later,the spinal cords were isolated and subjected to immunoblotting assay to determine the role of CaN in FK506-induced AMPA receptor modification.Results 1)After 7 consecutive days of intraperitoneal injection of FK506,the PWT and PWL of mice dropped significantly,reaching on day 7 as low as 22.3%±0.05%and 66.6%±0.05%of the control group,respectively(P<0.01).The FK506-treated mice displayed evident spontaneous pain behavior,presenting significantly increased licking activities(P<0.01).These results indicated that FK506-induced pain model was successfully established.Immunoblotting assay showed that the total expressions of GluA1 and GluA2 subunits in the spinal dorsal horn of the FK506 group remained unchanged in comparison with those of the Saline group.However,FK506 specifically induced an increase in the synaptic expression of GluA1.In addition,the phosphorylation levels of GluA1 at Ser845 and Ser831 in FK506-treated mice were significantly increased in comparison with those of the control group(P<0.05).2)Compared with those of the mice in the FK506+Saline group,the PWT and the PWL of mice in the FK506+CaN group were significantly increased(P<0.05).3)Compared with those of the FK506+Saline group,the synaptic expression of GluA1 were decreased in FK506+CaN group(P<0.01)and the phosphorylation levels of GluA1 at Ser845 and Ser831 were significantly downregulated(P<0.001).Conclusion The hyper-expression and hyperphosphorylation of GluA1 subunit in the spinal cord dorsal horn resulting from CaN inhibition contributes to the FK506-induced pain syndrome.FK506 induces the synaptic hyper-expression and hyperphosphorylation of GluA1 in the dorsal horn of the spinal cord through CaN inhibition,thereby inducing pain.

Objective:To investigate the efficacy of a SARS-CoV-2 recombinant protein vaccine as a booster dose.Methods:A new immunogen, namely RBD-sc-trimer, was designed by tandem repeating of single receptor binding domain (RBD) of SARS-CoV-2 spike (S) protein to mimic the trimeric form of RBD presented by the virus. The RBD-sc-trimer protein was expressed as a His-tagged fusion protein using a baculovirus expression system and purified by nickel affinity column. The purified protein was identified by Western blot. Its in vitro binding activity to human angiotensin converting enzyme 2 (hACE2) was analyzed by ELISA. The immunogenicity of RBD-sc-trimer as well as RBD proteins of other forms including RBD dimer (RBD-Fc), RBD monomer (RBD) and S protein trimer (S trimer) as a booster dose was evaluated in BALB/c mice. Results:In terms of both binding and neutralizing antibodies against SARS-CoV-2, RBD-sc-trimer showed an immunogenicity that was superior to that of RBD-Fc and RBD and close to the level of S trimer. The antibody response induced by RBD-sc-trimer was characterized as Th1-biased. Moreover, it displayed a stronger cross-neutralization activity against SARS-CoV-2 Beta, Delta and Omicron variants. The titer of neutralizing antibody against Omicron induced by RBD-sc-trimer only decreased by 9.1 folds relative to the prototype strain, while the antibody response induced by RBD-Fc and S trimer decreased by 68.4 and 70.8 folds, respectively.Conclusions:The recombinant protein, RBD-sc-trimer, which was capable of eliciting stronger humoral response in mice as a booster dose and showed the superiority in raising cross-reactive antibodies against SARS-CoV-2 variants over non-trimeric RBD forms, should be considered as an optimal immunogen for the development of more effective SARS-CoV-2 vaccines.

Islet β cell protection is one of the key strategies for diabetes treatment. The new antidiabetic drug sodium-glucose cotransporter 2(SGLT2)inhibitor decreases blood glucose by inhibiting glucose reabsorption in the renal tubule, independent of insulin. Various clinical studies have shown that SGLT2 inhibitors improve β cell function. Furthermore, animal experiments have indicated that SGLT2 inhibitors increase β cell mass. SGLT2 inhibitors promote islet regeneration through stimulating β cell proliferation, inhibiting β cell apoptosis and dedifferentiation, enhancing transdifferentiation of α cells to β cells, and initiating progenitor-derived β cell neogenisis. Indirect effects of metabolic improvement(i.e.lowering glucose, losing weight, improving lipid metabolism), inhibiting inflammatory reaction, inducing glucagon-like peptide-1 secreted from α cells, and regulating gene changes might be involved in the β cell protection of SGLT2 inhibitors.

Drug-device combination product, which comprises at least a drug and a medical device, has been proved to effectively reduce the risk of complications accompanied with conventional medical devices implantation, and has a great clinical success especially in implantable therapeutics. Herein, we firstly elaborated the definitions and requirements of drug-device combination product in different countries, then summarized the market application and research development of typical drug-device combination products. Technical problems and the trend of future development had also been analyzed.
Drug Delivery Systems/instrumentation* ; Equipment Design ; Prostheses and Implants

Objective:To investigate and understand the general situation and quality of life of migrant workers with pneumoconiosis, and analyze the influencing factors, so as to provide scientific basis for effective countermeasures to improve the quality of life of migrant workers with pneumoconiosis.Methods:In June 2019, 79 cases of migrant workers' pneumoconiosis diagnosed by Shandong Occupational Disease Hospital from March 2017 to August 2018 were selected as the study object by cluster random sampling method. Questionnaires and on-site visits were used to investigate the quality of life and its influencing factors. The questionnaire was administered by self-designed questionnaire and WHO quality of life questionnaire.Results:The farmer's pneumoconiosis patients are generally lower in culture. High school or above is only 6.33% (5/79) . Their economic income is low. The monthly income of less than 1000 RMB is 49.37% (39/79) . The disease was heavy and pneumoconiosis was 58.23% (46/79) . Pneumoconiosis patients without systematic treatment accounted for 69.62% (55/79) . Only 11.39% of rural workers with pneumoconiosis can timely increase or decrease clothing and wear masks to avoid respiratory irritation. Pneumoconiosis patients who smoked accounted for 77.22% (61/79) . The quality of life of the pneumoconiosis patients in the physiological, psychological, social and environmental fields were (10.40±2.31) , (11.40±2.82) , (11.46±3.03) and (8.38±3.37) respectively. The influencing factors of quality of life were pneumoconiosis stage, education level, economic income and smoking ( P< 0.05) . Conclusion:The quality of life of migrant workers with pneumoconiosis is generally low. The main factors that affect the quality of life of patients are disease severity (pneumoconiosis stage) , education level, economic income and smoking.

Objective:To investigate and understand the general situation and quality of life of migrant workers with pneumoconiosis, and analyze the influencing factors, so as to provide scientific basis for effective countermeasures to improve the quality of life of migrant workers with pneumoconiosis.Methods:In June 2019, 79 cases of migrant workers' pneumoconiosis diagnosed by Shandong Occupational Disease Hospital from March 2017 to August 2018 were selected as the study object by cluster random sampling method. Questionnaires and on-site visits were used to investigate the quality of life and its influencing factors. The questionnaire was administered by self-designed questionnaire and WHO quality of life questionnaire.Results:The farmer's pneumoconiosis patients are generally lower in culture. High school or above is only 6.33% (5/79) . Their economic income is low. The monthly income of less than 1000 RMB is 49.37% (39/79) . The disease was heavy and pneumoconiosis was 58.23% (46/79) . Pneumoconiosis patients without systematic treatment accounted for 69.62% (55/79) . Only 11.39% of rural workers with pneumoconiosis can timely increase or decrease clothing and wear masks to avoid respiratory irritation. Pneumoconiosis patients who smoked accounted for 77.22% (61/79) . The quality of life of the pneumoconiosis patients in the physiological, psychological, social and environmental fields were (10.40±2.31) , (11.40±2.82) , (11.46±3.03) and (8.38±3.37) respectively. The influencing factors of quality of life were pneumoconiosis stage, education level, economic income and smoking ( P< 0.05) . Conclusion:The quality of life of migrant workers with pneumoconiosis is generally low. The main factors that affect the quality of life of patients are disease severity (pneumoconiosis stage) , education level, economic income and smoking.

OBJECTIVE: To explore the effects and mechanisms of the long-snake moxibustion on ankylosing spondylitis (AS) based on Th17/Treg/Th1 immune imbalance. METHODS: A total of 60 AS patients were randomized into an observation group and a control group, 30 cases in each one. In the observation group, the long-snake moxibustion therapy was used on the acupoints of the governor vessel from Dazhui (GV 14) to Yaoshu (GV 2) as well as the bilateral Jiaji (EX-B 2) alternatively. The moxibustion was given once a day, for 7 days continuously as one course. There were 3 days at the interval between the courses and 4 courses were required. In the control group, the routine western medication was provided, the salazosulfapyridine combined with non-steroidal anti-inflammatory drugs were used, for 7 days continuous as one course. A total of 4 courses of medication were required. The enzyme linked immunosorbent assay (ELISA) was adopted to determine the levels of interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23) and tumor necrosis factor-α (TNF-α). The real-time quantification polymerase chain reaction (RT-PCR) was used to determine the mRNA expressions of the specific transcription factors, FoxP3 and T-bet of the helper 17 cells (Th17), regulatory T cells (Treg) and T helper 1 cells (Th1). The flow cytometry was applied to determine the rates of Treg, Th1 and Th17, as well as the changes of the inflammatory reaction index, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). The therapeutic effects were compared between the two groups. RESULTS: After treatment, the total effective rate was 93.3% (28/30) in the observation group, which was better than 86.7% (26/30) in the control group (<0.05). After treatment, the levels of CRP, ESR, IL-6, IL-17, IL-23 and TNF-α, as well as the rate of Th17 were reduced significantly as compared with those before treatment in the observation group (all <0.05). The mRNA expressions of FoxP3 and T-bet and the rates of Treg and Th1 were increased as compared with those before treatment (all <0.05). The change degree in the observation group was significant as compared with the control group (all <0.05). In the control group, the levels of CRP, ESR, IL-6, IL-17, IL-23 and TNF-α, as well as the rate of Th17 were reduced, and the mRNA expressions of FoxP3 and T-bet and the rates of Treg and Th1 were increased after treatment. But the changes were not significant as compared with those before treatment (all >0.05). CONCLUSION The long-snake moxibustion effectively relieves the clinical symptoms in AS patients and regulates the Th17/Treg/Th1 immune imbalance. Its effect target is probably related to the modulation of the AS immune derangement and the inflammatory responses induced by immune derangement so as to achieve the dual-positive regulatory effect.
Animals ; Humans ; Lymphocyte Count ; Moxibustion ; Snakes ; Spondylitis, Ankylosing ; therapy ; T-Lymphocytes, Regulatory ; Th1 Cells ; Th17 Cells

OBJECTIVETo verify the clinical safety of complete mesocolic excision (CME) and manufacture pathological large slices.

METHODSA prospective analysis clinical data of 85 right colon cancer in patients by the same group of surgeons at the Department of General Surgery, Beijing Friendship Hospital, Capital Medical University from January 2012 to December 2013 which were divided into two groups: CME group (n=39) and traditional radical operation group (n=46) by surgical approach. CME group and control group were compared the differences of clinic and pathologic variables, precise tissues morphometry, lymph nodes harvest, mesocolic area and so on. By comparison to operation time, blood loss, postoperative complications, flatus restoring time, drainage removal time and length of stay, the security of CME was analyzed. Statistical methods included independent sample t-test, Wilcoxon rank sum test and χ(2) test. In order to manufacture pathological large slices, the CME operation specimens were fixed. The large slices were stained by routine HE staining to detection of circumferential resection margin.

RESULTSMean number of total lymph nodes was increased obviously in CME group (26.8±1.9 vs. 23.2±3.4, t=4.261, P=0.000). Mean number of lymph nodes of stage Ⅰ, Ⅱ were different between two groups (25.8±3.6 vs. 18.2±4.5, 26.8±7.7 vs. 24.9±6.2, t=8.776, 2.802, P=0.000). The positive lymph nodes of CME group was higher than control group (4(7) vs. 1.5(2), P=0.032), above all with statistically significant difference. Comparing CME group with the control group, there were the larger area of mesentery ((15 555±1 263) mm(2) vs. (12 493±1 002) mm(2,) t=12.456, P=0.000), the greater distance between the tumor and the high vascular tie ((116±22) mm vs. (82±11) mm, t=9.295, P=0.000), the greater distance between the normal bowel and the high vascular tie ((92±17) mm vs. (74±10) mm, t=8.132, P=0.000) of CME, with statistically significant difference. There were no statistically significant differences from operation safety when CME group was compared with the control group. The pathological large slices of colon cancer were prepared successfully and dyed evenly than those large slices were used to observe whether the lymph tube and lymph node metastasis inside the mesocolon. Existence of direct tumor invasion could be confirmed by investigating the large slices. Cancer embolus in intravascular and micro infiltration in mesocolon also could be found.

CONCLUSIONSCME operation can get the standard excision according the mesocolic area and integrity, as well as to harvest the maximum number of lymph node. The clinical application of CME is safe and does not increase the risk of operation. Circumferential resection margins can be detected by pathological large slices.

Colectomy ; Colonic Neoplasms ; surgery ; Device Removal ; Humans ; Lymph Node Excision ; Lymph Nodes ; Lymphatic Metastasis ; Mesocolon ; surgery ; Operative Time ; Postoperative Complications ; Prospective Studies