Population Pharmacokinetics of Intranasal Dexmedetomidine in Infants and Young Children.

BACKGROUND: Intranasal dexmedetomidine provides noninvasive, effective procedural sedation for pediatric patients, and has been widely used in clinical practice. However, the dosage applied has varied fourfold in pediatric clinical studies. To validate an appropriate dosing regimen, this study investigated the pharmacokinetics of intranasal dexmedetomidine in Chinese children under 3 yr old. METHODS: Intranasal dexmedetomidine 2 µg · kg-1 was administered to children with simple vascular malformations undergoing interventional radiological procedures. A population pharmacokinetic analysis with data from an optimized sparse-sampling design was performed using nonlinear mixed-effects modeling. Clearance was modeled using allometric scaling and a sigmoid postmenstrual age maturation model. Monte Carlo simulations were performed to assess the different dosing regimens. RESULTS: A total of 586 samples from 137 children aged 3 to 36 months were included in the trial. The data were adequately described by a two-compartment model with first-order elimination. Body weight with allometric scaling and maturation function were significant covariates of dexmedetomidine clearance. The pharmacokinetic parameters for the median subjects (weight 10 kg and postmenstrual age 101 weeks) in the authors' study were apparent central volume of distribution 7.55 l, apparent clearance of central compartment 9.92 l · h-1, apparent peripheral volume of distribution 7.80 l, and apparent intercompartmental clearance 61.7 l · h-1. The simulation indicated that at the dose of 2 µg · kg-1, 95% of simulated individuals could achieve a target therapeutic concentration of 0.3 ng · ml-1 within 20 min, and the average peak concentration of 0.563 ng · ml-1 could be attained at 61 min. CONCLUSIONS: The pharmacokinetic characteristics of intranasal dexmedetomidine were evaluated in Chinese pediatric patients aged between 3 and 36 months. An evidence-based dosing regimen at 2 µg · kg-1 could achieve a preset therapeutic threshold of mild to moderate sedation that lasted for up to 2 h.

[A randomized controlled trial study of immunogenicity and safety of an inactivated SARS-CoV-2 vaccine in different immunization schedules].

Objective: To compare the immunogenicity and safety of an inactivated SARS-CoV-2 vaccine used for the vaccination in public security officers with different immunization schedules. Methods: From January to February, 2021, 405 public security officers in Taiyuan were randomly divided into 3 groups. Two doses of SARS-CoV-2 inactivated vaccine were injected according to the immunization schedule of 0-14 days, 0-21 days or 0-28 days, respectively. The nucleic acid of SARS-CoV-2 was detected by reverse transcription polymerase chain reaction. The neutralizing antibodies to SARS-CoV-2 were tested by microdose cytopathogenic efficiency assay of live virus. The GMT, seroconversion rate of SARS-CoV-2 neutralizing antibody and safety of the vaccine were analyzed for the 3 groups. Results: The seroconversion rate of SARS-CoV-2 neutralizing antibody was 100% in all the 3 groups. The SARS-CoV-2 neutralizing antibody level of 0-21 day group [166.70 (95%CI: 148.30-185.10)] was similar to that of 0-28 day group [179.50 (95%CI: 156.50-202.60)] (P>0.05), significantly higher than that of 0-14 day group [86.08 (95%CI: 72.36-99.80)] (P<0.001). The incidence rates of adverse reaction in the 3 groups were 1.48% (2/135), 0.74% (1/136) and 1.49% (2/134) respectively (P=0.750), all the adverse reactions were mild. Conclusions: The vaccination of inactivated SARS-CoV-2 vaccine with different immunization schedules in public security officers showed good safety and high seroconversion rate, and the GMTs of SARS-CoV-2 neutralizing antibody in 0-21 day group and 0-28 day group were higher than that in 0-14 day group.

Development, Characterization, and Evaluation of SLN-Loaded Thermoresponsive Hydrogel System of Topotecan as Biological Macromolecule for Colorectal Delivery.

BACKGROUND: Chemotherapeutic drugs cause severe toxicities if administered unprotected, without proper targeting, and controlled release. In this study, we developed topotecan- (TPT-) loaded solid lipid nanoparticles (SLNs) for their chemotherapeutic effect against colorectal cancer. The TPT-SLNs were further incorporated into a thermoresponsive hydrogel system (TRHS) (TPT-SLNs-TRHS) to ensure control release and reduce toxicity of the drug. Microemulsion technique and cold method were, respectively, used to develop TPT-SLNs and TPT-SLNs-TRHS. Particle size, polydispersive index (PDI), and incorporation efficiency (IE) of the TPT-SLNs were determined. Similarly, gelation time, gel strength, and bioadhesive force studies of the TPT-SLNs-TRHS were performed. Additionally, in vitro release and pharmacokinetic and antitumour evaluations of the formulation were done. RESULTS: TPT-SLNs have uniformly distributed particles with mean size in nanorange (174 nm) and IE of ~90%. TPT-SLNs-TRHS demonstrated suitable gelation properties upon administration into the rat's rectum. Moreover, drug release was exhibited in a control manner over an extended period of time for the incorporated TPT. Pharmacokinetic studies showed enhanced bioavailability of the TPT with improved plasma concentration and AUC. Further, it showed significantly enhanced antitumour effect in tumour-bearing mice as compared to the test formulations. CONCLUSION: It can be concluded that SLNs incorporated in TRHS could be a potential source of the antitumour drug delivery with better control of the drug release and no toxicity.

Real-Life State of Anti-Hepatitis B Virus Drug Choice in Child-Bearing Age Male Patients and Effect on Fertility and Fetal Safety.

Research on effects of anti-hepatitis B virus (HBV) nucleoside analogs on male fertility and birth defects is limited and safety of nucleoside analogs in pregnancy is still a concern. Chronic hepatitis B (CHB) patients in Guangdong province were surveyed using a structured questionnaire. We collected data including medication type, fertility, and birth defects. Moreover, a survey of the knowledge of antiviral nucleoside analogs safety in fertility of male patients was conducted among physicians nationwide. Semen samples of 30 patients were collected. We screened 1050 HBV-positive male patients. Reasons for not receiving antivirals in 150 patients were "did not meet criteria for antiviral therapy," fertility, and financial. Furthermore, 900 participants received antivirals (85.71%, 900/1050), including 792 patients with children and 15.15% (120/792) took anti-HBV treatment when preparing for pregnancy. Based on whether they received antiviral therapy during conception or not, we divided patients into two groups. In the child-bearing age group, 88.33% (106/120) of patients received telbivudine (LDT), whereas the other group mainly received entecavir (ETV) (87.20%, 586/672). No significant difference occurred in birth defect incidence rates between both groups. Furthermore, 558 physicians completed questionnaires. Reasons that influenced drug selection were "patient's condition," "fertility demand," "financial condition," and "compliance." Telbivudine was the first-choice drug (32.80%, 183/558) while tenofovir (TDF) was the second (2.69%, 15/558). Additionally, 61.47% of physicians considered telbivudine or tenofovir as the first choice for male patients who met antiviral criteria, whereas 19% suggested delayed therapy and follow-up until childbirth. No significant changes occurred in semen volume, concentration, mobility, and percentage before and after administration of anti-HBV nucleoside analogs, which did not affect male fertility and birth defect incidence while the desire for pregnancy influenced drug selection and timing of administration. Further research on the effects of analogs on male fertility and fetal safety is required.

A randomized controlled trial of oral chloral hydrate vs intranasal dexmedetomidine plus buccal midazolam for auditory brainstem response testing in children.

BACKGROUND: Moderate to deep sedation is required for an auditory brainstem response test when high-intensity stimulation is used. Chloral hydrate is the most commonly used sedative, whereas intranasal dexmedetomidine is increasingly used in pediatric non-painful procedural sedations. OBJECTIVE: The aim of this study was to compare the sedation success rate after oral chloral hydrate at 50 mg kg-1 and intranasal dexmedetomidine at 3 µg kg-1 plus buccal midazolam at 0.1 mg kg-1 for an auditory brainstem response test. METHODS: Children who required an auditory brainstem response test were recruited and randomly assigned to receive oral chloral hydrate at 50 mg kg-1 and intranasal placebo, or intranasal dexmedetomidine at 3 µg kg-1 with buccal midazolam 0.1 mg kg-1 . The primary outcome was the rate of successful sedation for auditory brainstem response tests. RESULTS: Fifty-seven out of 82 (69.5%) were successfully sedated after chloral hydrate, while 70 out of 78 (89.7%) children were successfully sedated with dexmedetomidine plus midazolam combination, with the odd ratio (95% CI) for successful sedation between dexmedetomidine plus midazolam combination and chloral hydrate estimated to be 3.84 (1.61-9.16), P = 0.002. Dexmedetomidine plus midazolam was associated with quicker onset with median onset time 15 (IQR 11.0-19.8) for dexmedetomidine plus midazolam and 20 (IQR 15.0-27.0) for chloral hydrate respectively, with difference between median (95% CI) of 5 [3-8], P < 0.0001). The behavior observed during drug administration of intranasal dexmedetomidine and buccal midazolam was better that of the children who had oral chloral hydrate. No children required oxygen therapy or medical intervention for hemodynamic disturbances in this study and the incidence of hypotension and bradycardia was similar. CONCLUSION: Intranasal dexmedetomidine plus buccal midazolam was associated with higher sedation success with deeper level of sedation, with similar discharge time and adverse event rate when compared to chloral hydrate.

The effect of the heart rate lowering drug Ivabradine on hemodynamics in atherosclerotic mice.

The heart rate lowering drug Ivabradine was shown to improve cardiac outcome in patients with previous heart failure. However, in patients without heart failure, no beneficial effect of Ivabradine was observed. Animal studies suggested a preventive effect of Ivabradine on atherosclerosis which was due to an increase in wall shear stress (WSS), the blood flow-induced frictional force exerted on the endothelium, triggering anti-inflammatory responses. However, data on the effect of Ivabradine on WSS is sparse. We aim to study the effect of Ivabradine on (i) the 3D WSS distribution over a growing plaque and (ii) plaque composition. We induced atherosclerosis in ApoE-/- mice by placing a tapered cast around the right common carotid artery (RCCA). Five weeks after cast placement, Ivabradine was administered via drinking water (15 mg/kg/day) for 2 weeks, after which the RCCA was excised for histology analyses. Before and after Ivabradine treatment, animals were imaged with Doppler Ultrasound to measure blood velocity. Vessel geometry was obtained using contrast-enhanced micro-CT. Time-averaged WSS during systole, diastole and peak WSS was subsequently computed. Ivabradine significantly decreased heart rate (459 ± 28 bpm vs. 567 ± 32 bpm, p < 0.001). Normalized peak flow significantly increased in the Ivabradine group (124.2% ± 40.5% vs. 87.3% ± 25.4%, p < 0.05), reflected by an increased normalized WSS level during systole (110.7% ± 18.4% vs. 75.4% ± 24.6%, p < 0.05). However, plaque size or composition including plaque area, relative necrotic core area and macrophage content were not altered in mice treated with Ivabradine compared to controls. We conclude that increased WSS in response to Ivabradine treatment did not affect plaque progression in a murine model.

Temporal and spatial changes in wall shear stress during atherosclerotic plaque progression in mice.

Wall shear stress (WSS) is involved in atherosclerotic plaque initiation, yet its role in plaque progression remains unclear. We aimed to study (i) the temporal and spatial changes in WSS over a growing plaque and (ii) the correlation between WSS and plaque composition, using animal-specific data in an atherosclerotic mouse model. Tapered casts were placed around the right common carotid arteries (RCCA) of ApoE-/- mice. At 5, 7 and 9 weeks after cast placement, RCCA geometry was reconstructed using contrast-enhanced micro-CT. Lumen narrowing was observed in all mice, indicating the progression of a lumen intruding plaque. Next, we determined the flow rate in the RCCA of each mouse using Doppler Ultrasound and computed WSS at all time points. Over time, as the plaque developed and further intruded into the lumen, absolute WSS significantly decreased. Finally at week 9, plaque composition was histologically characterized. The proximal part of the plaque was small and eccentric, exposed to relatively lower WSS. Close to the cast a larger and concentric plaque was present, exposed to relatively higher WSS. Lower WSS was significantly correlated to the accumulation of macrophages in the eccentric plaque. When pooling data of all animals, correlation between WSS and plaque composition was weak and no longer statistically significant. In conclusion, our data showed that in our mouse model absolute WSS strikingly decreased during disease progression, which was significantly correlated to plaque area and macrophage content. Besides, our study demonstrates the necessity to analyse individual animals and plaques when studying correlations between WSS and plaque composition.

Composition and Diversity of Communities of Dactylogyrus spp. In Wild and Farmed Goldfish Carassius auratus.

Species composition and diversity of dactylogyrids were compared on gills of wild and cultured goldfish (silver crucian carp) Carassius auratus from 3 naturally populated lakes and 3 stocked aquaculture ponds in the Hubei province of China to examine the differences in the gill parasite community between these natural and farmed waters. Of the 7 Dactylogyrus spp. detected, all were found in lakes and 5 in ponds, with Dactylogyrus inexpectatus and Dactylogyrus anchoratus being absent from ponds. No significant correlation was found between the species richness and habitat area or host size, nor was there a significant difference in mean species richness between lakes (0.41-0.65) and ponds (0.30-0.76). Brillouin's diversity in lakes (0.049-0.067) was higher than that in ponds (0.024-0.046), but not significantly so. Although the diversity of parasite communities was higher in wild goldfish, higher mean abundance of some Dactylogyrus spp. was found in cultured goldfish. Based on Bray-Curtis similarity, it was difficult to differentiate parasite communities in lakes from those in ponds at the infracommunity level, whereas the 3 lakes and Guanqiao pond differed markedly from the remaining 2 ponds at the component community level. Although infracommunities differed among waterbodies, no effects of fish length or waterbody type were found on infracommunity or component community structure. Together, these results suggest that abundance and species richness of Dactylogyrus spp. on goldfish in lakes and farm ponds are influenced by habitat-specific environmental factors.

[Significance of v-raf murine sarcoma viral oncogene homologue B1 in rheumatoid arthritis].

OBJECTIVE: To detect serum v-raf murine sarcoma viral oncogene homologue B1 (BRAF) protein levels and to investigate their clinical significance in rheumatoid arthritis (RA) patients. METHODS: Serum samples were obtained from 78 RA patients, 32 osteoarthritis (OA) patients, 16 systemic lupus erythematosus (SLE) patients, 16 gout patients, 16 ankylosing spondylitis (AS) patients, 16 Sjogren syndrome (SS) patients and 30 healthy controls. BRAF protein in the sera was examined by enzyme-linked immunosorbent assay (ELISA). The associations between BRAF levels and the clinical features including age, sex, disease duration, swelling joints, tenderness joints, duration of moning stiffness, joint deformity, visual assessment scale (VAS) and extra articular manifestations and laboratory parameters including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), disease activity score in 28 joints (DAS28), anti-cyclic citrullinated peptide (CCP) antibody, antikeratin antibody, antnuclear antibody (ANA), immunoglobulin and cytokines, such as TNF-α, IL-1ß, IL-6 and IL-17A in RA patients were evaluated. Data analyses were performed by using SPSS 19.0 program. RESULTS: The serum BRAF protein levels in the RA patients were significantly higher than those of other rheumatic diseases groups including OA, SLE, AS, SS, gout patients and healthy controls, the P value was 0.002, <0.001, <0.001, <0.001, 0.001 and <0.001 respectively. The level of serum BRAF protein in the RA patients showed a positive correlation with the rheumatoid factor (P=0.009) and IgA levels (P=0.006), but no correlation with clinical features, such as age and duration or other laboratory parameters, including CRP, ESR, anti-CCP antibody, IgM, IgG, TNF-α, IL-1ß, IL-6 and IL-17A. The RA patients were further divided into normal levels of BRAF protein group and elevated levels of BRAF protein group. Compared with the clinical features and laboratory indexes of normal and elevated levels of BRAF protein groups in the RA patients, there was no significant difference between the two groups in age, duration, DAS28, CRP, ESR, RF, anti-CCP, IgA, IgG, IgM, TNF-α or IL-6. CONCLUSION: The elevated level of BRAF protein in the RA patients showed that BRAF might play a role in the pathogenesis of RA. Further researches on BRAF gene expression may help to clarify the role of BRAF in RA.

Bisphosphonates therapy for osteoarthritis: a meta-analysis of randomized controlled trials.

High-turnover type bone metabolism derangement has been considered to be one of the major causes of osteoarthritis (OA). Bisphosphonates can attach to hydroxyapatite binding sites on bony surfaces, particularly those which are undergoing active bone resorption. To evaluate the effectiveness of bisphosphonates in OA treatment, literature databases were searched from inception to February 28, 2016 for clinical studies of bisphosphonates for OA treatment. All randomized controlled trials in which bisphosphonates therapy was compared with a placebo or a conventional medication, were selected. 15/1145 studies were eligible for analysis, which included 3566 participants. Bisphosphonates therapy improved pain, stiffness and function significantly in OA assessed by the Western Ontario and McMaster Universities Arthritis Index scale (MD = 4.59; 95 % CI 2.83-6.34; P < 0.00001; MD = 1.43; 95 % CI 0.83-2.23; P = 0.0005; MD = 2.01; 95 % CI 1.27-2.75; P < 0.00001). Bisphosphonates also reduced osteophyte score significantly (MD = -0.51; 95 % CI -0.84 to -0.19; P = 0.002). However, no significant differences were found in subjective improvement, osteoarthritis progression, the number of required acetaminophen treatment or joint replacement. In conclusion, bisphosphonates therapy is effective in relieving pain,stiffness and accelerating functional recovery in OA. Limitations of the studies we analysed included the differences in duration of bisphosphonates use, the doses and types of bisphosphonates and the lack of long-term data on OA joint structure modification after bisphosphonates therapy. More targeted studies are required to evaluate on the effectiveness of bisphosphonates for OA treatment.

Anxiety-like behavior and dysregulation of miR-34a in triple transgenic mice of Alzheimer's disease.

OBJECTIVE: MicroRNAs (miRNAs) play an important role in the development of the brain and also implicated in the pathogenesis of neurological diseases such as Alzheimer's disease (AD). Recent studies implied that dysregulation of miRNAs is involved in neuropsychiatric disorders such as anxiety disorder in AD. MATERIALS AND METHODS: In this study, behavioral experiments such as open field test, elevated plus maze test and light-dark box test were performed to evaluate anxiety-like behaviors in a triple transgenic mouse model of AD (3xTg-AD mice), and Q-PCR was used to measure the change of miR-34a expression. RESULTS: Behavioral tests revealed anxiety-like behaviors in 3xTg-AD mice. Q-PCR assay showed significantly elevated expression of miR-34a in the hippocampus of 3xTg-AD mice compared with the age- and gender-matched wild-type mice. Western-blot analysis showed that the expression of metabotropic glutamate receptor 7 (GRM7) but not fibroblast growth factor-2 (FGF2), two anxiety disorder-related target genes of miR-34a, was significantly decreased in hippocampus of 3xTg-AD mice compared with the wild-type mice. CONCLUSIONS: We concluded that anxiety-like behavior occurred in 3xTg-AD mice with an involvement of miR-34a/GRM7.

Radiation-enhancing effect of sodium glycididazole in patients suffering from non-small cell lung cancer with multiple brain metastases: A randomized, placebo-controlled study.

PURPOSE: Median survival of patients with brain metastases from non-small cell lung cancer is poor. This study was to investigate the radiation-enhancing effect of sodium glycididazole combined with whole-brain radiotherapy of multiple brain metastases from non-small cell lung cancer. PATIENTS AND METHODS: Sixty-four patients with multiple brain metastases from non-small cell lung cancer were included: the study group (n=32) received whole-brain radiotherapy combined with sodium glycididazole at a dose of 700mg/m(2) intravenous infusion 30minutes before radiotherapy, three times a week; the control group (n=32) only received whole-brain radiotherapy. The primary end point was central nervous system (CNS) progression-free survival and overall survival. The treatment-related toxicity was also recorded. RESULTS: The CNS disease control rate was better (90.6% vs 65.6%, P=0.016) in the study group than in the control group at 3 month of follow-up. The median CNS progression-free survival time was longer in the study group than in the control group (7.0 months vs 4.0 months, P=0.038). There was no significant difference of the median overall survival time between the study group and the control group (11.0 months vs 9.0 months, P=0.418). On the other hand, the treatment-related toxicity showed no statistically significant difference between these two groups (P>0.05). CONCLUSIONS: The study indicated that sodium glycididazole was an effective, promising radiation-enhancing agent that improved CNS disease control rate, extended the median CNS progression-free survival time and was well tolerated in patients suffering from non-small cell lung cancer with multiple brain metastases.

Neutral alpha-1,4-glucosidase and fructose levels contribute to discriminating obstructive and nonobstructive azoospermia in Chinese men with azoospermia.

Nowadays, whether neutral alpha-1,4-glucosidase (NAG) and fructose levels are contributed to discriminating obstructive and nonobstructive azoospermia in Chinese azoospermic patients remains unclear. In this study, we retrospectively analysed the levels of NAG and fructose in 229 patients with obstructive azoospermia and 415 patients with nonobstructive azoospermia from three different medical central. Results indicated that NAG and fructose levels in patients with nonobstructive azoospermia were significantly higher compared with those with obstructive azoospermia (P < 0.05). According to the reference value of NAG and fructose defined by the World Health Organization (WHO, 2010), decreased level of NAG was observed in 77.3% of patients with obstructive azoospermia, which was significantly higher than those with nonobstructive azoospermia (55.2%, P < 0.0001). Low level of fructose was observed in 48.0% of patients with obstructive azoospermia, which is also obviously higher than those with nonobstructive azoospermia (31.8%, P < 0.0001). Moreover, the decrease of both NAG and fructose was only recorded in 3.7% of patients with SCO syndrome, 5.0% of patients with severe hypospermatogenesis and 18.2% of patients with maturation arrest. Therefore, our results indicated that NAG and fructose levels are contributed to discriminating obstructive and nonobstructive azoospermia in Chinese patients based on the histological types of testes.

Copy number variations of HLA-I and activation of NKp30 pathway determine the sensitivity of gastric cancer cells to the cytotoxicity of natural killer cells.

Nude mice are important in vivo model for characterization of cell malignancy behavior; however, many cancer cells fail to form tumors in it. Understanding this defective mechanism may provide novel insights into tumorigenesis and how tumor cells escape innate immunity. Whole-genome sequencing was conducted on two gastric cancer (GC) cells, BGC823 and AGS, which do and do not form tumors in nude mice, to identify their genomic differences relevant to natural killer (NK) cells. We found that the tumorigenic capacity of human GC cell lines was dependent on the recruitment and activation of NK cells in xenograft tumors. We used whole-genome sequence (WGS) on GC cell lines to identify potential genes controlling susceptibility to NK-mediated killing. The tumorigenic cell line BGC823 expressed high levels of HLA-I because of copy gain and was resistant to NK cell killing. In contrast, another cell line AGS expressing low levels of HLA-I with activated NKp30/MAPK/IL-12 (interleukin-12) or IL-2 (interleukin-2) pathway was susceptible to NK lysis. Treatment of tumor bearing mice with systemic administration of IL-12 in combination with intratumor injection of anti-HLA-I antibody significantly increased NK cell recruitment into xenograft tumors, which became sensitive to NK killing, resulting in reduced tumor progression. In human GC specimens, decreased HLA-I expression and increased NK cells surrounding tumor cells were correlated with decreased metastasis potential and better prognosis of patients. Our results provide a mechanistic basis for GC cells to escape NK lysis and a promising prospect of NK immunotherapy for GC cells.

Interleukin-21 Induces Proliferation and Proinflammatory Cytokine Profile of Fibroblast-like Synoviocytes of Patients with Rheumatoid Arthritis.

Fibroblast-like synoviocytes (FLS) play a pivotal role in the pathogenesis of rheumatoid arthritis (RA) through aggressive proliferation and invasion, and certain proinflammatory cytokines may affect synoviocyte proliferation. To evaluate whether interleukin-21 (IL-21) could promote proliferation and proinflammatory cytokine production by RA-FLS, immunohistochemistry and immunoblotting were performed to observe the expression of IL-21 receptor (IL-21R) in synovial tissues and FLS from RA and osteoarthritis (OA) patients. The MTS assay was used to analyse RA-FLS proliferation. The concentrations of IL-6 and tumour necrosis factor-α (TNF-α) in culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). The signalling pathways triggered by IL-21 were characterized by immunoblotting. IL-21R was upregulated in the synovial tissues and FLS of RA patients as compared with OA patients. IL-21 stimulated RA-FLS proliferation and promoted the production of TNF-α and IL-6 and blockade of IL-21/IL-21R pathway with IL-21R.Fc attenuated IL-21-induced proliferation and secretion of TNF-α and IL-6. Moreover, IL-21 induced activation of the ERK1/2, PI3K/AKT and STAT3 pathways, and blockade of these pathways attenuated IL-21-induced proliferation and secretion of TNF-α and IL-6. These results suggest that IL-21 could promote RA-FLS proliferation and production of proinflammatory cytokines. Therefore, therapeutic strategies targeting IL-21 might be effective for the treatment of RA.