Intradermal acupuncture in the treatment of rheumatoid arthritis with liver and kidney deficiency syndrome - A sham-controlled, randomized, clinical trial.

BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) is called "immortal cancer", and it affects the quality of life, disability rate and even the survival of patients. This study aimed to observe the clinical efficacy, and adverse reactions of intradermal acupuncture (IA) in the treatment of RA patients with liver and kidney deficiency syndrome. MATERIALS AND METHODS: 132 RA patients were split into an IA group and a sham IA group at a 1:1 ratio. Both groups were assessed before and after the intervention with the assessments: a traditional Chinese medicine (TCM) syndrome evaluation, the Health Assessment Questionnaire (HAQ), the Disease Activity Score 28 (DAS28) and serum C-reactive protein (CRP). RESULTS: There was a statistically significant difference in TCM syndrome evaluation, HAQ, DAS28, and CRP between both groups before and after treatment (P < 0.01). The improvement of TCM syndrome evaluation (95% CI [1.14(0.38-1.89)]; P = 0.001), HAQ (95% CI [2.00(1.00-3.00)]; P = 0.003), and DAS28 (95% CI [0.11(0.02-0.20)]; P = 0.021) in the IA group was more obvious than that in the sham IA group (P < 0.05), except for CRP (95% CI [0.50(- 2.09 to 7.08)], P = 0.786). The difference in CRP outcome changes between the two groups was not statistically significant (P > 0.05). Both groups had comparable results in the implementation of RA in the upper and lower extremity acupoints and did not differ due to different sites (IA group: P = 0.852; sham IA group: P = 0.861). The comparison of effective rate of the upper limb as well as that of the lower limb was statistically significant (P = 0.001). Besides, patients reported no adverse effects. CONCLUSION: The IA intervention was associated with a promising effect on the decrease in RA disease activity and delayed overall disease progression.

Periplogenin inhibits pathologic synovial proliferation and infiltration in rheumatoid arthritis by regulating the JAK2/3-STAT3 pathway.

Rheumatoid arthritis (RA) is an autoimmune disease that affects joints, causing inflammation, synovitis, and erosion of cartilage and bone. Periplogenin is an active ingredient in the anti-rheumatic and anti-inflammatory herb, cortex periplocae. We conducted a study using a CIA model and an in vitro model of fibroblast-like synoviocytes (FLS) induced by Tumor Necrosis Factor-alpha (TNF-α) stimulation. We evaluated cell activity, proliferation, and migration using the CCK8 test, EDU kit, and transwell assays, as well as network pharmacokinetic analysis of periplogenin targets and RA-related effects. Furthermore, we measured inflammatory factors and matrix metalloproteinases (MMPs) expression using ELISA and qRT-PCR assays. We also evaluated joint destruction using HE and Safranin O-Fast Green Staining and examined the changes in the JAK2/3-STAT3 pathway using western blot. The results indicated that periplogenin can effectively inhibit the secretion of inflammatory factors, suppress the JAK2/3-STAT3 pathway, and impede the proliferation and migration of RA FLS. Thus, periplogenin alleviated the Synovial inflammatory infiltration of RA.

A patient with refractory proliferative lupus nephritis treated with telitacicept: A case report.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Lupus nephritis (LN) is a common type of organ damage which occurs in SLE patients and is characterized by recurrent proteinuria. Activation of B lymphocytes can lead to refractory LN, which is an important pathogenic factor in SLE. B lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL) are predominantly produced by myeloid cells (monocytes, dendritic cells, neutrophils, etc) to regulate B lymphocyte function. Telitacicept was the first dual-targeting biological drug which targeted both BLyS and APRIL. Telitacicept has passed a phase II clinical trial and has since been approved for the treatment of SLE. CASE PRESENTATION: We report a case of SLE confirmed by renal biopsy as proliferative lupus nephritis (PLN) with massive proteinuria, which was treated with telitacicept (European League Against Rheumatism / American College of Rheumatology 2019 standard). During the 19 months of follow-up, the patient's renal function was stable, massive proteinuria was relieved, and creatinine and blood pressure did not increase. CONCLUSIONS: During the 19 months of telitacicept treatment (160 mg once weekly), PLN reduced blood system damage and proteinuria without increasing the risk of infection.

The Underlying Mechanism of Duanteng Yimu Decoction in Inhibiting Synovial Hyperplasia in Rheumatoid Arthritis.

Dysregulation of microRNAs (miRNAs) is associated with the pathogenesis of rheumatoid arthritis (RA). Our previous studies confirmed that Duanteng Yimu decoction (DTYMT) effectively inhibits RA fibroblast-like synoviocyte (FLS) proliferation. In this study, we investigated the influence of DTYMT on miR-221 in RA individuals. Hematoxylin-eosin (HE) staining was performed to assess histopathological alterations in collagen-induced arthritis (CIA) mice. The expression of miR-221-3p and TLR4 in PBMC, FLS, and cartilage was measured by RT-qPCR. In the in vitro experiments, DTYMT-containing serum was incubated with FLS-transfected miR-221 mimic or inhibitor. CCK-8 was performed to determine FLS proliferation, and the secretion of IL-1ß, IL-6, IL-18, and TNF-α was quantified by ELISA assay. In addition, the regulation of miR-221 expression on FLS apoptosis was assessed using flow cytometry. Finally, western blot was employed to reflect TLR4/MyD88 protein levels. HE results showed that DTYMT effectively reduced synovial hyperplasia in the joints of CIA mice. RT-qPCR assay of FLS and cartilage of the model group showed that miR-221-3p and TLR4 significantly increased compared with those in the normal group. All outcomes were improved by DTYMT. The miR-221 mimic reversed the inhibitory effect of DTYMT-containing serum on FLS proliferation, the release of IL-1ß, IL-18, IL-6, and TNF-α, and FLS apoptosis, as well as TLR4/MyD88 protein levels. The results showed that miR-221 promotes the activity of RA-FLS by activating TLR4/MyD88 signaling, and DTYMT treats RA by reducing miR-221 in CIA mice.

Radiomics features based on internal and marginal areas of the tumor for the preoperative prediction of microsatellite instability status in colorectal cancer.

Objectives: To explore whether the preoperative CT radiomics can predict the status of microsatellite instability (MSI) in colorectal cancer (CRC) patients and identify the region with the most stable and high-efficiency radiomics features. Methods: This retrospective study involved 230 CRC patients with preoperative computed tomography scans and available MSI status between December 2019 and October 2021. Image segmentation and radiomic feature extraction were performed as follows. First, slices with the maximum tumor area (region of interest, ROI) were manually contoured. Subsequently, each ROI was shrunk inward by 1, 2, and 3 mm, respectively, where the remaining ROIs were considered as the internal region of the tumor (named as IROI1, IROI2, and IROI3), and the shrunk regions were considered as marginal regions of the tumor (named as MROI1, MROI2, and MROI3). Finally, radiomics features were extracted from each of the ROI. The intraclass correlation coefficient and least absolute shrinkage and selection operator method were used to choose the most reliable and relevant features of MSI status. Clinical, radiomics, and combined clinical radiomics models have been established. Calibration curve and decision curve analyses (DCA) were generated to explore the correction effect and assess the clinical applicability of the above models, respectively. Results: In the testing cohort, the radiomics model based on IROI3 yielded the highest average area under the curve (AUC) value of 0.908, compared with the remaining radiomics models. Additionally, hypertension and N stage were considered as clinically independent factors of MSI status. The combined clinical radiomics model achieved excellent diagnostic efficacy (AUC: 0.928; sensitivity: 0.840; specificity: 0.867) in the testing cohort, as well as favorable calibration and clinical utility by calibration curve and DCA analyses. Conclusions: The IROI3 model, which is based on a 3-mm shrink in the largest areas of the tumor, could noninvasively reflect the heterogeneity and genetic instability within the tumor. This suggests that it is an important biomarker for the preoperative prediction of MSI status. The model can extract more robust and effective radiomics features, which lays a foundation for the radiomics study of hollow organs, such as in CRC.

Study on the effect and mechanism of quercetin in treating gout arthritis.

Quercetin is widely found in natural plants, especially Chinese herbal plants. It has been used to treat arthritis in China for thousands of years. However, the effects and mechanisms of quercetin in the treatment of gout arthritis (GA) remain unclear. We aimed to verify the treatment of GA with quercetin and investigate the underlying mechanism. A combination of network pharmacology and experiments was used to reveal the mechanism of quercetin in the treatment of GA. Potential targets of quercetin and gout were identified. Then, the protein-protein interaction network for the common targets between quercetin and gout was constructed and the core targets were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses for the common targets were performed to elucidate the pharmacological functions and mechanisms associated with quercetin treatment in GA. Finally, a monosodium urate-induced GA rat model was used to validate the predicted mechanisms in network pharmacology. Seventy-two common targets were identified. KEGG analysis revealed that treatment of GA with quercetin predominantly involved the interleukin (IL)-17, tumor necrosis factor (TNF), mitogen-activated protein kinase, and phosphoinositide 3-kinase-Akt signaling pathways. In an experimental validation, quercetin attenuated ankle joint inflammation-induced bone destruction and histological lesions. It also diminished the expression of IL-6, IL-17A, and IL-17F in the IL-17 pathway, and regulated the release of RAR-related orphan receptor gamma t,IL-17E, IL-1ß, IL-6, TNF-α, Foxp3, and transforming growth factor-beta 1. The collective findings implicate quercetin as a valuable alternative drug for the treatment of GA.

Case report: JAKi and TNFi dual therapy is a potential treatment strategy for difficult-to-treat rheumatoid arthritis.

Rheumatoid arthritis (RA) is a heterogeneous chronic disease. RA patients should start disease modifying anti-rheumatic drugs (DMARDs) therapy immediately after diagnosis. If first-line treatment with conventional synthetic DMARDs does not relieve the disease, biology and targeted synthetic DMARDs are options for patients. Patients can switch to different types of biological and targeted synthetic DMARDs if remission is not achieved. However, for patients with difficult-to-treat RA, achieving disease stabilization after the failure of multiple biological and targeted synthetic DMARDs is a clinical challenge that needs to be addressed. As distinct cytokine pathways, the benefits and challenges of dual therapy are worth discussing. As the most extensively used biologic DMARDs, adalimumab is an anti-tumor necrosis factor monoclonal antibody used to treat RA. Tofacitinib, as a Janus Kinase inhibitor, is an orally administered targeted synthetic DMARDs that involved in the regulation of immune responses by directly or indirectly inhibiting cytokine pathways. This report describes a successful case of a 48-year-old woman with difficult-to-treat RA who treated with Tofacitinib combined with adalimumab. She had been on glucocorticosteroid for a long time, but had persistent joint pain and fatigue. At more than one year of follow-up, her Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-ESR) remained in complete remission, and she discontinued her glucocorticosteroid medications. Also, she did not develop a mycobacterial tuberculosis infection, herpes zoster, and new-onset cardiovascular events.

Nitidine chloride inhibits fibroblast like synoviocytes-mediated rheumatoid synovial inflammation and joint destruction by targeting KCNH1.

OBJECTIVE: Nitidine chloride (NC), a natural small molecular compound from traditional Chinese herbal medicine zanthoxylum nitidum, has been shown to exhibit anti-tumor effect. However, its role in autoimmune diseases such as rheumatoid arthritis (RA) is unknown. Here, we investigate the effect of NC in controlling fibroblast-like synoviocytes (FLS)-mediated synovial inflammation and joint destruction in RA and further explore its underlying mechanism(s). METHODS: FLSs were separated from synovial tissues obtained from patients with RA. Protein expression was analyzed by Western blot or immunohistochemistry. Gene expression was measured using quantitative RT-PCR. ELISA was used to measure the levels of cytokines and MMPs. Cell proliferation was detected using EdU incorporation. Migration and invasion were evaluated by Boyden chamber assay. RNA sequencing analysis was used to identify the target of NC. Collagen-induced arthritis (CIA) model was used to evaluate the in vivo effect of NC. RESULTS: NC treatment reduced the proliferation, migration, invasion, and lamellipodia formation but not apoptosis of RA FLSs. We also demonstrated the inhibitory effect of NC on TNF-α-induced expression and secretion of IL-6, IL-8, CCL-2, MMP-1 and MMP-13. Furthermore, we identified KCNH1, a gene that encodes ether-à-go-go-1 channel, as a novel targeting gene of NC in RA FLSs. KCNH1 expression was increased in FLSs and synovial tissues from patients with RA compared to healthy controls. KCNH1 knockdown or NC treatment decreased the TNF-α-induced phosphorylation of AKT. Interestingly, NC treatment ameliorated the severity of arthritis and reduced synovial KCNH1 expression in mice with CIA. CONCLUSIONS: Our data demonstrate that NC treatment inhibits aggressive and inflammatory actions of RA FLSs by targeting KCNH1 and sequential inhibition of AKT phosphorylation. Our findings suggest that NC might control FLS-mediated rheumatoid synovial inflammation and joint destruction, and be a novel therapeutic agent for RA.

Case Report: Treatment of Anti-MDA5-Positive Amyopathic Dermatomyositis Accompanied by a Rapidly Progressive Interstitial Lung Diseases With Methylprednisolone Pulse Therapy Combined With Cyclosporine A and Hydroxychloroquine.

Introduction: Patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive amyopathic dermatomyositis (ADM) often develop rapidly progressive interstitial lung diseases (RP-ILD), with poor treatment success. Many studies have shown that this is the main cause of death in patients with anti-MDA5 antibody-positive ADM. Case Presentation: A 37-years-old woman developed a cough, shortness of breath, and a rash on both hands, which resembled Gottron's signs. Upon laboratory examination, the results were as follows: antinuclear antibody (ANA) positive; anti-Ro52 antibody positive; and anti-MDA5 antibody positive. Pulmonary high-resolution CT (HRCT) scan showed pulmonary interstitial inflammatory changes, and mediastinal and subcutaneous emphysema. She was finally diagnosed with anti-MDA5 antibody-positive ADM accompanied by RP-ILD. She was first given high-dose-steroid pulse therapy with methylprednisolone (500 mg per day for 3 days) followed by methylprednisolone (40 mg, daily), cyclosporine A (100 mg, twice per day), and hydroxychloroquine (200 mg, twice per day). Since her discharge from our hospital in March of 2018, she has maintained the methylprednisolone therapy (tapered to 10 mg daily), cyclosporine A (100 mg, twice per day), and hydroxychloroquine (200 mg, twice per day). Outcomes: Pulmonary HRCT scans taken on 4, 9, and 26 months after her discharge from our hospital showed that the interstitial pneumonitis had significantly improved and that mediastinal and subcutaneous emphysema had been gradually absorbed. The patient can now participate in regular work and activities of daily living. Conclusion: The treatment of methylprednisolone pulse therapy combined with cyclosporine A and hydroxychloroquine may be an option for the RP-ILD accompanied by anti-MDA-positive ADM. After the acute phase, this combination therapy strategy is helpful to the disease control of patients.

Leonurine Regulates Treg/Th17 Balance to Attenuate Rheumatoid Arthritis Through Inhibition of TAZ Expression.

Leonurine, an active alkaloid extracted from Herba leonuri, is reported to have potent anti-inflammatory activity against rheumatoid arthritis (RA). However, the molecular mechanism of action of leonurine in RA remains poorly understood. In this study, we detected 3,425 mRNAs differentially expressed between CD4+ T cells of RA patients and those of healthy individuals using microarray raw data mining. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that transcriptional coactivator with PDZ-binding motif (TAZ) regulates a variety of biological processes including T-helper (Th)-17 cell development, and was thus selected for functional verification. In a naïve CD4+ T cell differentiation assay, we found that TAZ overexpression was associated with impaired balance between T regulatory (Treg) and Th17 cells in vitro. TAZ overexpression increased the levels of the pro-inflammatory cytokines interleukin (IL)-17, IL-1ß, and tumor necrosis factor (TNF)-α and decreased that of the anti-inflammatory cytokine IL-10. Leonurine treatment had a direct recovery effect on the impaired balance and reduced the expression of TAZ and led to normalization of IL-17, IL-1ß, and TNF-α and IL-10. Furthermore, IL-6 was found to promote the expression of TAZ and receptor activator of nuclear factor kappa-B ligand (RANKL), and RANK. Leonurine significantly inhibited TAZ-mediated expression of RANKL, and RANK and IL-6 in synovial fibroblasts. We conclude that the therapeutic effect of leonurine was through suppression of TAZ led to restoration of Treg/Th17 balance and suppression of synovial fibroblast action.

Use of the Gout Impact Scale to Evaluate Quality of Life in Chinese Subjects with Gout: A Cross-Sectional Study.

BACKGROUND To use a gout-specific quality of life (QoL) tool, the Gout Impact Scale (GIS), to evaluate characteristics of gout affecting QoL in subjects with gout. MATERIAL AND METHODS In this cross-sectional study, 169 individuals with gout completed the 24-item GIS and a general questionnaire regarding gout characteristics. The reliability and validity of the GIS were verified by Cronbach's a and exploratory factor analysis, respectively. The impact of gout characteristics on the QoL of subjects with gout was assessed by stepwise multiple regression analysis. RESULTS The 169 subjects with gout included 149 (88.2%) men and 20 (11.8%) women, of median age 43 years. The reliability of the GIS was appropriate (0.84-0.90), except for Gout Medication Side Effects (0.69) and Unmet Gout Treatment Need (0.59). Exploratory factor analysis showed that construct validity was acceptable, with a cumulative variance contribution rate of 5 common factors of 70.09% and factor loading >0.5 between each pair of items of the GIS. Univariate analysis showed that male sex was positively correlated with Well-being During Attack (p<0.05), and that source of medical expenses, current cigarette use and drinking were significantly correlated with Unmet Gout Treatment Need (p<0.05 each). A family history of gout, gout flares, and attack frequency were significantly correlated with total GIS, Well-being During Attack, and Gout Concern during Attack (p<0.05 each). Multivariate analysis suggested that history of gouty arthritis, acute attack and attack frequency had a considerable impact on QoL (p<0.05 each). CONCLUSIONS The GIS showed acceptable reliability and validity in identifying associations between poor QoL and gout characteristics.

Serum Uric Acid Shows Inverted "U" Type Correlation with Osteoporosis in Chinese Ankylosing Spondylitis Patients: A Retrospective Study.

BACKGROUND This study was to investigate the correlation between osteoporosis and serum uric acid in ankylosing spondylitis (AS) patients, and to further identify potential factors that might be associated with osteoporosis in AS patients. MATERIAL AND METHODS We included 182 AS patients, consisted of 143 male patients and 39 female patients, who visited our hospital from January 1, 2014 to December 31, 2018. We used dual-energy x-ray absorptiometry to measure bone mineral density (BMD) of orthotopic lumbar vertebrae in patients with AS. The gender, age, disease duration, BMD, T-score, Z-score, uric acid, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood platelet (PLT), and status of treatment with biologics of the patients were collected. Then, the Spearman correlation coefficient and multivariate liner regression analysis were applied to identify the relationship between the factors and BMD, T-score, and Z-score in AS patients. RESULTS Male AS patients between the ages of 16 and 30 years old had a higher risk of osteoporosis (P<0.05). AS patients with uric acid value between 300-360 µmol/L had the highest BMD, T-score, and Z-score. The BMD had a positive correlation with age and disease duration (P<0.01) while had a negative correlation with PLT (P<0.05). BMD in AS patients with elevated ESR was significantly (P<0.05) lower than in AS patients with normal ESR. There were no significant differences in BMD between AS patients with elevated CRP and the patients with normal CRP and PLT. Treatment with TNFi (tumor necrosis factor alpha inhibitor) did not improve BMD in AS patients. CONCLUSIONS The relationship between uric acid and BMD in AS patients was observed as inverted "U"-type. Keeping uric acid within 300-360 µmol/L might be helpful in preventing AS patients from developing osteoporosis.

[Nivolumab-induced hypothyroidism: A case report].

Nivolumab is an anti-programmed cell death (anti-PD-1) monoclonal antibody, which is a new drug for tumor immunotherapy. A 73-year-old female patient with colorectal cancer 3 years after surgery was treated in the Endocrinology Department of Third Xiangya Hospital, Central South University, who developed severe hypothyroidism resulting from treatment with nivolumab. After 4 months treatment of nivolumab, this patient presented with symptoms such as fatigue, dizziness, jaundice and palpebral edema, with decreased levels of FT3 and FT4 and elevated levels of TSH. Subsequently, nivolumab treatment was terminated. This patient's symptoms were relieved and thyroid function returned to normal after thyroxine replacement therapy. The clinical diagnosis was considered to be nivolumab-induced autoimmune thyroid damage, which was an immune-related adverse reaction in the treatment.

25-hydroxycholesterol down-regulates oxysterol binding protein like 2 (OSBPL2) via the p53/SREBF2/NFYA signaling pathway.

Oxysterol Binding Protein Like 2 (OSBPL2) is a lipid-binding protein implicated in various cellular processes. Previous studies have shown that depression of OSBPL2 significantly increases the level of cellular 25-hydroxycholesterol (25-OHC) which regulates the expression of lipid-metabolism-related genes. However, whether 25-OHC can regulate the expression of OSBPL2 remains unanswered. This study aimed to explore the molecular mechanism of 25-OHC regulating the expression of OSBPL2. Using dual-luciferase reporter assay, we found a decrease of nuclear transcription factor Y subunit alpha (NFYA) bound with OSBPL2 promoter when HeLa cells were treated with 25-OHC. Furthermore, transcriptome sequencing and RNA interference results revealed that the p53/sterol regulatory element binding transcription factor 2 (SREBF2) signaling pathway was involved in the NFYA-dependent transcription of OSBPL2 induced by 25-OHC. Based on these results, we concluded that pleomorphic adenoma gene 1 (PLAG1) and NFYA participated in the basal transcription of OSBPL2 and that 25-OHC decreased the transcription of OSBPL2 via the p53/SREBF2/NFYA signaling pathway. 25-OHC will accumulate over time in OSBPL2 knockdown cells. These results may provide a new insight into the deafness caused by OSBPL2 mutation.

Betulinic acid inhibits the migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis.

The aggressive phenotype displayed by fibroblast-like synoviocytes (FLSs) contributes to cartilage and bone destruction in rheumatoid arthritis (RA). Betulinic acid has been demonstrated to have a positive therapeutic effect on tumor, inflammation and immune disorder, however, the effects of betulinic acid on RA FLSs have not been verified. Therefore, in the present study, we observed the effect of betulinic acid on the migration and invasion of RA FLSs and explored its underlying signal mechanisms. Our results showed that betulinic acid treatment suppressed the migration, invasion and reorganization of the actin cytoskeleton of RA FLSs. In addition, we found that the mRNA expression of IL-1ß, IL-6, IL-8 and IL-17A were markedly down-regulated by treatment with betulinic acid in TNF-α-induced RA FLSs. To gain insight into the molecular mechanisms, we evaluated the effect of betulinic acid on NF-κB activation in RA FLSs. The results indicated that betulinic acid treatment reduced the TNF-α-induced activation of NF-κB signal pathway and the NF-κB nuclear accumulation. We also observed that treatment with betulinic acid attenuated synovial inflammation and joint destruction in mice with CIA. Taken together, these results suggest that betulinic acid inhibits the migration and invasion of RA FLSs by blocking NF-κB signal pathway activation.

Homozygous nonsense mutation Trp28X in the LHB gene causes male hypogonadism.

PURPOSE: The purpose of this study was to investigate a novel mutation in the luteinizing hormone beta-subunit (LHB) gene in one male patient with hypogonadism due to selective luteinizing hormone (LH) deficiency. METHODS: Sanger sequencing of one 28-year-old man born to consanguineous parents was performed. Treatment with human chorionic gonadotropin (hCG) (2000 IU, twice a week) was initiated for 3 months, followed by 5000 IU weekly to date. RESULTS: We identified a novel c.84G>A[p.W28X] nonsense LHB mutation. The W28X mutation produces a truncated LHB peptide of seven amino acids, which prevents the synthesis of intact LH. After 40 days of treatment with hCG, the patient exhibited a few spermatozoa in the semen. Treated for 6 months, the patient exhibited normal seminal parameters. CONCLUSIONS: We identified a novel mutation in the LHB gene in a male patient with hypogonadism and provided evidence that LHB nonsense mutation can cause selective LH deficiency. We reconfirmed hCG treatment may restore male fertility due to LHB mutation.

Kaempferol inhibits the migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes by blocking activation of the MAPK pathway.

In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLSs) play an essential role in cartilage destruction. Aggressive migration and invasion by FLSs significantly affect RA pathology. Kaempferol has been shown to inhibit cancer cell migration and invasion. However, the effects of kaempferol on RA FLSs have not been investigated. Our study aimed to determine the effects of kaempferol on RA both in vitro and in vivo. In vitro, cell migration and invasion were measured using scratch assays and the Boyden chamber method, respectively. The cytoskeletal reorganization of RA FLSs was evaluated by immunofluorescence staining. Matrix metalloproteinase (MMP) levels were measured by real-time PCR, and protein expression levels were measured by western blotting. In vivo, the effects of kaempferol were evaluated in mice with CIA. The results showed that kaempferol reduced migration, invasion and MMP expression in RA FLSs. In addition, we demonstrated that kaempferol inhibited reorganization of the actin cytoskeleton during cell migration. Moreover, kaempferol dramatically suppressed tumor necrosis factor (TNF)-α-induced MAPK activation without affecting the expression of TNF-α receptors. We also demonstrated that kaempferol attenuated the severity of arthritis in mice with CIA. Taken together, these results suggested that kaempferol inhibits the migration and invasion of FLSs in RA by blocking MAPK pathway activation without affecting the expression of TNF-α receptors.

Leonurine attenuates fibroblast-like synoviocyte-mediated synovial inflammation and joint destruction in rheumatoid arthritis.

Objective: To explore the role of leonurine in the regulation of synovial inflammation and joint destruction inRA. Methods: Fibroblast-like synoviocytes were isolated from synovial tissue from RA patients. Pro-inflammatory cytokine and MMP expression was evaluated using real-time PCR and a cytometric bead array. Cell migration and invasion in vitro were measured using the Boyden chamber method and the scratch assay, respectively. Protein expression was measured by western blotting. Nuclear factor kappa B (NF-κB) nuclear translocation was detected by immunofluorescence. The in vivo effect of leonurine was evaluated in mice with CIA. Results: Leonurine treatment significantly decreased the production of pro-inflammatory cytokines (IL-1ß, IL-6, IL-8 and TNFα) and MMPs (MMP-1 and MMP-3) and suppressed the migration and invasion of RA fibroblast-like synoviocytes. The molecular analysis revealed that leonurine impaired TNFα-induced NF-κB signalling by inhibiting the phosphorylation and degradation of inhibitor of NF-κB alpha (IκBα) and subsequently preventing the nuclear translocation of the NF-κB p65 subunit. Leonurine also inhibited the p38 and Jun N-terminal kinase mitogen-activated protein kinases signalling pathways without affecting ERK signalling. Intraperitoneal injection of leonurine reduced synovial inflammation, joint destruction and the serum IL-1ß, IL-6 and TNFα levels in mice with CIA. Conclusion: Our findings show that leonurine reduces synovial inflammation and joint destruction in RA through the NF-κB and mitogen-activated protein kinases pathways. Leonurine has potential as a therapeutic agent for RA.

Novel LOVD databases for hereditary breast cancer and colorectal cancer genes in the Chinese population.

The Human Variome Project (HVP) is an international consortium of clinicians, geneticists, and researchers from over 30 countries, aiming to facilitate the establishment and maintenance of standards, systems, and infrastructure for the worldwide collection and sharing of all genetic variations effecting human disease. The HVP-China Node will build new and supplement existing databases of genetic diseases. As the first effort, we have created a novel variant database of BRCA1 and BRCA2, mismatch repair genes (MMR), and APC genes for breast cancer, Lynch syndrome, and familial adenomatous polyposis (FAP), respectively, in the Chinese population using the Leiden Open Variation Database (LOVD) format. We searched PubMed and some Chinese search engines to collect all the variants of these genes in the Chinese population that have already been detected and reported. There are some differences in the gene variants between the Chinese population and that of other ethnicities. The database is available online at http://www.genomed.org/LOVD/. Our database will appear to users who survey other LOVD databases (e.g., by Google search, or by NCBI GeneTests search). Remote submissions are accepted, and the information is updated monthly.