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Aims: This study investigated insulinoma‐associated‐2 autoantibody (IA‐2A) and zinc transporter 8 autoantibody (ZnT8A) distribution in patients with type 1 diabetes (T1D) and latent autoimmune diabetes (LAD) and the autoantibodies' association with clinical characteristics and HLA‐DR‐DQ genes. Materials and Methods: This cross‐sectional study recruited 17,536 patients with diabetes from 46 hospitals across China. A total of 189 patients with T1D and 58 patients with LAD with IA‐2A positivity, 126 patients with T1D and 86 patients with LAD with ZnT8A positivity, and 231 patients with type 2 diabetes (T2D) were selected to evaluate islet autoantibodies, clinical phenotypes, and HLA‐DR‐DQ gene frequency. Results: IA‐2A was bimodally distributed in patients with T1D and LAD. Patients with low IA‐2A titre LAD had lower fasting C‐peptide (FCP) (p < 0.01), lower postprandial C‐peptide (PCP) (p < 0.001), and higher haemoglobin A1c (HbA1c) levels (p < 0.05) than patients with T2D. Patients with high IA‐2A titre LAD were younger than patients with low IA‐2A titre LAD (p < 0.05). Patients with low IA‐2A titre T1D had lower FCP (p < 0.01), lower PCP (p < 0.01), and higher HbA1c levels (p < 0.05) than patients with high IA‐2A titre LAD. HLA‐DR‐DQ genetic analysis demonstrated that the frequency of susceptible HLA haplotypes was higher in IA‐2A‐positive patients (p < 0.001) than in patients with T2D. Patients with high ZnT8A titre LAD had lower FCP (p = 0.045), lower PCP (p = 0.023), and higher HbA1c levels (p = 0.009) and a higher frequency of total susceptible haplotypes (p < 0.001) than patients with low ZnT8A titre LAD. Conclusions: IA‐2A in patients with T1D and LAD was bimodally distributed, and the presence of IA‐2A could demonstrate partial LAD clinical characteristics. ZnT8A titre had a certain predictive value for islet functions in patients with LAD. [ABSTRACT FROM AUTHOR]

Context: This study applied the Swedish novel data-driven classification in Chinese newly diagnosed diabetic patients and validated its adoptability.Objective: This study aimed to validate the practicality of the Swedish diabetes regrouping scheme in Chinese adults with newly diagnosed diabetes.Design: Patients were classified into 5 subgroups by K-means and Two-Step methods according to 6 clinical parameters.Setting: Ambulatory care.Patients: A cross-sectional survey of 15 772 patients with adult-onset newly diagnosed diabetes was conducted in China from April 2015 to October 2017.Intervention: None.Main Outcome Measures: Six parameters including glutamate decarboxylase antibodies (GADA), age of onset, body mass index (BMI), glycated hemoglobin A1c (HbA1c), homoeostatic model assessment 2 estimates of β-cell function (HOMA2-B) and insulin resistance (HOMA2-IR) were measured to calculate the patient subgroups.Results: Our patients clustered into 5 subgroups: 6.2% were in the severe autoimmune diabetes (SAID) subgroup, 24.8% were in the severe insulin-deficient diabetes (SIDD) subgroup, 16.6% were in the severe insulin-resistance diabetes (SIRD) subgroup, 21.6% were in the mild obesity-related diabetes (MOD) subgroup and 30.9% were in the mild age-related diabetes (MARD) subgroup. When compared with the Swedish population, the proportion of SIDD subgroup was higher. In general, Chinese patients had younger age, lower BMI, higher HbA1c, lower HOMA2-B and HOMA2-IR, and higher insulin use but lower metformin usage than the Swedish patients.Conclusion: The Swedish diabetes regrouping scheme is applicable to adult-onset diabetes in China, with a high proportion of patients with the severe insulin deficient diabetes. Further validations of long-term diabetes complications remain warranted in future studies. [ABSTRACT FROM AUTHOR]

During abscisic acid (ABA) signaling, reversible phosphorylation controls the activity and accumulation of class III SNF1-RELATED PROTEIN KINASE 2s (SnRK2s). While protein phosphatases that negatively regulate SnRK2s have been identified, those that positively regulate ABA signaling through SnRK2s are less understood. In this study, Arabidopsis thaliana mutants of Clade E Growth-Regulating 1 and 2 (EGR1/2), which belong to the protein phosphatase 2C family, exhibited reduced ABA sensitivity in terms of seed germination, cotyledon greening, and ABI5 accumulation. Conversely, overexpression increased these ABA-induced responses. Transcriptomic data revealed that most ABA-regulated genes in egr1 egr2 plants were expressed at reduced levels compared with those in Col-0 after ABA treatment. Abscisic acid up-regulated EGR1/2, which interact directly with SnRK2.2 through its C-terminal domain I. Genetic analysis demonstrated that EGR1/2 function through SnRK2.2 during ABA response. Furthermore, SnRK2.2 de-phosphorylation by EGR1/2 was identified at serine 31 within the ATP-binding pocket. A phospho-mimic mutation confirmed that phosphorylation at serine 31 inhibited SnRK2.2 activity and reduced ABA responsiveness in plants. Our findings highlight the positive role of EGR1/2 in regulating ABA signaling, they reveal a new mechanism for modulating SnRK2.2 activity, and provide novel insight into how plants fine-tune their responses to ABA., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

Icariin (ICA) is a small molecule drug capable of promoting cartilage repair and ameliorating inflammation. Loading ICA into a biomaterial scaffold for cartilage tissue engineering will thus potentially enhance the biological functionality of the engineered scaffold. In this study, short fibers processed from electrospun poly(l-lactide- co -caprolactone) (PLCL) fibers which were prior coated with polydopamine (PDA), were mixed with citric acid doped chitosan solution (CC) for preparing short fibers reinforced chitosan hydrogel (PDA@PLCL/CC) by a freeze-thawing combined freeze-drying method. Thereafter, ICA was loaded into the PDA@PLCL/CC scaffold through physical adsorption to generate a newly engineered biomimetic cartilage scaffold (ICA-PDA@PLCL/CC). Finally, ICA-mediated chondrogenic and ameliorated inflammatory effects of the ICA-PDA@PLCL/CC scaffold were examined in vitro using rabbit chondrocytes. The results showed that the ICA-free PDA@PLCL/CC scaffold possessed appropriate pore size and porosity (> 80%), high water absorbance capacity and improved mechanical performance, and also promoted chondrocyte proliferation and adhesion. The ICA-laden ICA-PDA@PLCL/CC scaffold was evidenced to maintain cytomorphology, upregulate the expression of chondrogenic gene ( sox-9 ), glycosaminoglycan gene ( gag ), and type Ⅱ collagen gene ( col Ⅱ ) as well as the synthesis of the cartilage matrix. In the presence of a simulated inflammation, the ICA-PDA@PLCL/CC scaffold was found to reduce chondrocyte fibrosis, effectively downregulate the expression of proinflammatory factors interleukin-6 ( il-6 ), interleukin-1 ( il-1 ), and inducible nitric oxide synthase ( inos ) in chondrocytes. It can also reduce matrix metalloproteinase-3 ( mmp-3 ) expression and promote the synthesis of the extracellular matrix glycosaminoglycan (GAG) and type II collagen (Col II). The newly developed ICA-PDA@PLCL/CC scaffold may find applications in the regeneration and repair of cartilage defects.

Objective: To examine the expression of heparin binding-epidermal growth factor-like growth factor (HB- EGF) in paclitaxel- resistant ovarian cancer and elucidate the relationship between HB-EGF and the resistance of ovarian cancer to paclitaxel., Methods: The human ovarian carcinoma cell line A2780 and the paclitaxel- resistant human ovarian carcinoma cell line A2780/Taxol were cultured in vitro. Western blot was used to dectect the expression of HB-EGF protein in A2780 and A2780/Taxol groups. The A2780 cells were treated with cross- reacting material 197 (CRM197 and A2780 + CRM197 group) or dimethyl sulphoxide (DMSO; A2780 group), while the A2780/Taxol cells were treated with CRM197 (A2780/Taxol+CRM197 group) or DMSO (A2780/Taxol group). The effects of CRM197 on growth and proliferation was tested by methyl thiazolyl tetrazolium ( MTT) and the results were showed as absorbance (A). The effects of CRM197 on cell cycles was tested by flow cytometry, while the effects of CRM197 on apoptosis was examined by caspase- 3 activity assay and the results were showed as p- nitroaniline(pNa). In animal experiment, four groups of cells were inoculated to BALB/c nude mouse subcutaneously to observe tumor formation ability following CRM197 treatment. Immunohistochemistry was used to determine the expression of HB-EGF protein in A2780 and A2780/Taxol group., Results: The expression level of HB-EGF protein in A2780/Taxol group (2.11 ± 0.41) was significantly higher than that of A2780 group (0.75 ± 0.20; P < 0.01). The inhibition effect of CRM197 on the cell growth of A2780+CRM197 and A2780/Taxol+CRM197 group was accompanied by the acceleration of CRM197 concentration(P < 0.01). When CRM197≥1 µg/ml, the inhibition effect of CRM197 on the cell growth of A2780/Taxol+CRM197 group was significantly higher than that in A2780/Taxol group(P < 0.05). In cell cycle experiment, CRM197 induced the cell-cycle arrest at the G0/G1 phase in A2780+CRM197 cells[(67 ± 4)%] compared with A2780 cells[(54 ± 6)%; P < 0.01], while CRM197 significantly induced the cell-cycle arrest at the G0/G1 phase in A2780/Taxol+CRM197 cells [(72 ± 4)%] compared with A2780/Taxol cells [(24 ± 8)%; P < 0.01]. CRM197 treatment in A2780+CRM197 group [(40 ± 6) µmol/L] led to the acceleration of the caspase-3 activity when compared to A2780 group [(6 ± 6) µmol/L; P < 0.01], while CRM197 treatment in A2780/Taxol+CRM197 group [(66 ± 12) µmol/L] led to significant acceleration of the caspase-3 activity when compared to A2780 group [(9 ± 6) µmol/L; P < 0.01]. In experiments in vivo, the expression scores of HB- EGF protein in A2780/Taxol tumors (10.8 ± 3.3) were higher than that in A2780 tumors (5.0 ± 2.2; P < 0.01). The tumor size and tumor weight of the A2780/Taxol + CRM197 group were both higher than those of the A2780+CRM197 group [(546 ± 85) mm³ vs (1 355 ± 119) mm³, (0.56 ± 0.09)g vs(1.31 ± 0.27)g; all P < 0.01]. The CRM197 inhibition rate of the A2780+ CRM197 and A2780/Taxol + CRM197 group were 43% and 68% respectively, showed that CRM197 significantly suppressed the growth of A2780/Taxol xenografts in vivo(P < 0.01)., Conclusions: HB-EGF is over-expressed in paclitaxel-resistant ovarian cancer and may be contributes to drug resistance. Inhibition of HB- EGF expression potently enhances apoptosis and inhibit the growth of paclitaxel- resistant ovarian cancer, shedding light on the HB-EGF-targeted therapy options for chemoresistant ovarian cancer patients.