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• Inflammatory MDSCs are expanded in RA patients and arthritic mice. • The frequencies of MDSCs correlated strongly with disease severity and Th17 response in RA patients. • TPT inhibited the expression of arginase-1 in MDSCs. • TPT reduces the severity of arthritis and the frequency of MDSCs effectively. • MDSCs may function as a novel and effective therapeutic target for TPT in RA. Triptolide (TPT) is widely used in the treatment of rheumatoid arthritis (RA). However, its regulatory mechanisms are not fully understood. This study demonstrated that Myeloid-derived suppressor cells (MDSCs) were expanded in both RA patients and arthritic mice. The frequency of MDSCs was correlated with RA disease severity and T helper 17 (Th17) responses. MDSCs from RA patients promoted the polarization of Th17 cells in vitro , which could be substantially attenuated by blocking arginase-1 (Arg-1). TPT inhibited the differentiation of MDSCs, particularly the monocytic MDSCs (M-MDSCs) subsets, as well as the expression of Arg-1 in a dose dependent manner. Alongside, TPT treatment reduced the potential of MDSCs to promote the polarization of IL-17+ T cell in vitro. Consistently, TPT immunotherapy alleviated adjuvant-induced arthritis (AIA) in a mice model, and reduced the frequency of MDSCs, M-MDSCs and IL-17+ T cells simultaneously. The presented data suggest a pathogenic role of MDSCs in RA and may function as a novel and effective therapeutic target for TPT in RA. [ABSTRACT FROM AUTHOR]

We evaluated simple laboratory variables to discriminate COVID-19 from bacterial pneumonia or influenza and for the prospective grading of COVID-19. Multivariate logistic regression and receiver operating characteristic curve were used to estimate the diagnostic performance of the significant discriminating variables. A comparative analysis was performed with different severity. The leukocytosis (P = 0.017) and eosinopenia (P = 0.001) were discriminating variables between COVID-19 and bacterial pneumonia with area under the curve (AUC) of 0.778 and 0.825. Monocytosis (P = 0.003), the decreased lymphocyte-to-monocyte ratio (P < 0.001), and the increased neutrophil-to-lymphocyte ratio (NLR) (P = 0.028) were predictive of influenza with AUC of 0.723, 0.895, and 0.783, respectively. Serum amyloid protein, lactate dehydrogenase, CD3+ cells, and the fibrinogen degradation products had a good correlation with the severity of COVID-19 graded by age (≥50) and NLR (≥3.13). Simple laboratory variables are helpful for rapid diagnosis on admission and hierarchical management of COVID-19 patients. • Laboratory features help differential diagnosis and the grade of COVID-19. • Leukocytosis and eosinopenia discriminate COVID-19 from bacterial pneumonia. • Monocytosis, NLR, and LMR distinguish COVID-19 from influenza. • Age, NLR, SAA, LDH, CD3+ cells, and FDP assist the stratification of COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: Circular RNA (circRNAs) are a type of non-coding RNA (ncRNAs) with a wealth of functions. Recently, circRNAs have been identified as important regulators of diabetic kidney disease (DKD), owing to their stability and enrichment in exosomes. However, the role of circRNAs in exosomes of tubular epithelial cells in DKD development has not been fully elucidated., Methods: In our study, microarray technology was used to analyze circRNA expression in cell supernatant exosomes isolated from HK-2 cells with or without high glucose (HG) treatment. The small interfering RNAs (siRNA) and plasmid overexpression were used to validate functions of differentially expressed circRNAs., Results: We found that exosome concentration was higher in HG-stimulated HK-2 cells than in controls. A total of 235 circRNAs were significantly increased and 458 circRNAs were significantly decreased in the exosomes of the HG group. In parallel with the microarray data, the qPCR results showed that the expression of circ&#95;0009885, circ&#95;0043753, and circ&#95;0011760 increased, and the expression of circ&#95;0032872, circ&#95;0004716, and circ&#95;0009445 decreased in the HG group. Rescue experiments showed that the effects of high glucose on regulation of CCL2, IL6, fibronetin, n cadherin, e cadherin and epcam expression can be reversed by inhibiting or overexpressing these circRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analyses indicated that circRNA parental genes are associated with glucose metabolism, lipid metabolism, and inflammatory processes, which are important in DKD development. Further analysis of circRNA/miRNA interactions indicated that 152 differentially expressed circRNAs with fold change (FC) ≥1.5 could be paired with 43 differentially expressed miRNAs, which are associated with diabetes or DKD., Discussion: Our results indicate that exosomal circRNAs may be promising diagnostic and therapeutic biomarkers, and may play a critical role in the progression of DKD., Competing Interests: The authors declare that they have no conflicts of interest in this work., (© 2023 Sha et al.)

Increasing reports on the significance of dietary patterns in reproduction have arisen from both animal and human studies, suggesting an interactive association between nutrition and male fertility. The aim of this study was to investigate the effects of curcumin supplementation on low-carbohydrate-diet-induced metabolic dysfunction, testicular antioxidant capacity, apoptosis, inflammation and spermatogenesis in male mice. Male C57BL/6 mice were fed a normal diet (AIN-93M group, n = 12) and a low-carbohydrate diet for 12 weeks (LC group, fed with low-carbohydrate diet, n = 48), and mice randomly chosen from the LC group were later fed their original diet (LC group, n = 12). This diet was changed to AIN-93M feed (LC/AIN-93M group, n = 12), a ketogenic diet (LC/KD group, n = 12), or a ketogenic diet treated with curcumin supplementation for the final 6 weeks (LC/KDCu group, n = 12). A poor sperm morphology and mean testicular biopsy score (MTBS) were observed in the LC and LC/KD groups, but they were eliminated by the normal diet or ketogenic diet with curcumin. The LC group exhibited a lower testicular testosterone level and a lower 17β-HSD activity and protein expression. This also enhanced apoptosis protein expressions in testis tissue, including Bax/BCl 2 , cleaved caspase 3, PARP and NF-κB. Meanwhile, we found a statistically significant increase in lipid peroxidation and decreased superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase levels in the LC group. Our study indicated that a replacement of a normal diet or ketogenic diet supplemented with curcumin attenuated poor semen quality and reduced testosterone levels by the LC diet by reducing oxidative stress.

Background: For patients who treated with tacrolimus after kidney transplant, therapeutic drug monitoring is essential to improve their prognosis. However, previous detection methods have limitations, such as the overestimation and unacceptable bias in the immunoassays. Precision medicine has been challenged. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is recognized as the gold standard due to its accuracy and specificity, but lack of throughput and complex process limits its clinical application. Therefore, an accurate, simple and high throughput method for tacrolimus monitoring is needed for clinical practice., Methods: A modified LC-MS/MS method was introduced and validated. Whole blood samples were prepared by a one-step protein precipitation method. Chromatographic separation was achieved using a Phenomenex Kinetex 2.6 μm XB-C18 2.1 × 50 mm column with a total run time of 3.5 min to avoid matrix effect. An electrospray ionization source (ESI) was used in positive ion multiple reaction monitoring (MRM) mode for mass spectrometric detection. In order to protect the mass spectrometer, only part of the sample after LC separation was allowed to enter the mass spectrum, through a two HPLC systems coupled one mass spectrometry design. In this way, the instrument throughput is also improved and realizing the detection of 2 samples within 3.5 min and carried out a shorter analyzing time for each sample of 1.75 min. Additionally, we calculated tacrolimus-intrapatient variant (Tac-IPV) based on this modified method and assessed the prognostic value of Tac-IPV in Chinese kidney transplant patients., Results: The LC-MS/MS was modified by streamlining the procedure and increasing the throughput. The method proved to be accurate and reproducible with all performance parameters suitably meeting the clinical requirements over a calibration ranged from 0.37 to 42.90 ng/mL. Parameters such as linearity, limit of quantification (LoQ) and dilution integrity were validated with a clinical reportable range from 0.37 to 343.20 ng/mL, which was particularly useful for high drug concentrations patients (rare but very serious). Both cross-contamination and matrix effects were negligible. Clinical data of 83 patients showed that Tac-IPV was associated with poor kidney transplant outcome in Chinese (Hazard Ratio (HR) = 3.96, 4.75; 95% Cl: 1.10-14.21, 1.23-18.36; P < 0.05)., Conclusions: This modified LC-MS/MS method possessed high throughput and simple sample preparation, allowing it to meet daily clinical needs. At the same time, Tac-IPV based on this modified LC-MS/MS had excellent prognostic value in kidney transplantation. These advantages have great significance for the individualized treatment of Chinese kidney transplant patients and broad application of Tac-IPV., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Objective: Long-term acupoint stimulation (LAS), also called embedding acupuncture, is a modified acupuncture technique. The preliminary results have demonstrated its efficacy in body-weight control. However, the low quality of available trials limited its application. This study aimed to evaluate the efficacy and safety of LAS in body-weight control by using a randomized, parallel, sham-controlled clinical trial design., Methods: This was a randomized, single-blind, sham-controlled clinical trial including 84 adult participants (18-60 years) with a body mass index (BMI) of ≥ 24 kg/m 2 conducted in three general hospitals in Shanghai, China. Participants were equally assigned to receive LAS or sham LAS (SLAS) once per 10 days, eight times in total. After completion, an additional intervention with a 3-month follow-up period was set to examine the continued effect of LAS. The primary outcome was the change in body weight from baseline to treatment endpoint within the intention-to-treat (ITT) analysis. Secondary outcomes contained changes in waist-to-hip ratio (WHR), lipid metabolism, and visceral and subcutaneous adipose tissues., Results: From 14 May 2018 to 03 November 2019, 84 participants out of 201 screened individuals met the eligibility criteria, were randomized, and were analyzed (42 participants in each group). From baseline to treatment endpoint, the body-weight reduction in the LAS group was significantly larger than in the sham control (net difference: 1.57 kg, 95% CI: 0.29-2.86, p = 0.012). The superior weight reduction effect persisted in the follow-up period (net difference: 3.20 kg, 95% CI: 1.17-5.21, p = 0.001). LAS therapy also showed improvement in triglyceride and subcutaneous adipose tissue (SAT) compared with sham control. One participant in the LAS group reported a slightly uncomfortable and tingling sensation after the additional intervention. No other adverse events (AEs) were documented., Conclusion: LAS, a modified acupuncture technique, is safe and effective in body-weight control. It could be used as an alternative choice to classical acupuncture for obesity management., Clinical Trial Registration: [www.chictr.org.cn], identifier [ChiCTR1800015498]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dai, Wang, Zhang, Wang, Zheng, Li, Zhou, Zhou and Ji.)

The metabolic characteristics of COVID-19 disease are still largely unknown. Here, 44 patients with COVID-19 (31 mild COVID-19 patients and 13 severe COVID-19 patients), 42 healthy controls (HC), and 42 patients with community-acquired pneumonia (CAP), were involved in the study to assess their serum metabolomic profiles. We used widely targeted metabolomics based on an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The differentially expressed metabolites in the plasma of mild and severe COVID-19 patients, CAP patients, and HC subjects were screened, and the main metabolic pathways involved were analyzed. Multiple mature machine learning algorithms confirmed that the metabolites performed excellently in discriminating COVID-19 groups from CAP and HC subjects, with an area under the curve (AUC) of 1. The specific dysregulation of AMP, dGMP, sn -glycero-3-phosphocholine, and carnitine was observed in the severe COVID-19 group. Moreover, random forest analysis suggested that these metabolites could discriminate between severe COVID-19 patients and mild COVID-19 patients, with an AUC of 0.921. This study may broaden our understanding of pathophysiological mechanisms of COVID-19 and may offer an experimental basis for developing novel treatment strategies against it., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Li, Lu, Yu, Zhang, Ke, Zhang and Li.)

Background: Induction chemotherapy (IC) can alleviate locoregionally advanced nasopharyngeal carcinoma (LA-NPC), but effectiveness differs between patients, toxicity is problematic, and effective blood-based IC efficacy predictors are lacking. Here, we aimed to identify biomarkers for early identification of IC beneficiaries., Methods: Sixty-four pairs of matched plasma samples collected before and after IC from LA-NPC patients including 34 responders and 30 non-responders, as well as 50 plasma samples of healthy individuals, were tested using data-independent acquisition mass spectrometry. The proteins associated with clinical traits or IC benefits were investigated by weighted gene co-expression network analysis (WGCNA) and soft cluster analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional annotations were performed to determine the potential function of the identified proteins. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of candidate biomarkers in predicting IC beneficiaries., Results: Compared with healthy individuals, 1027 differentially expressed proteins (DEPs) were found in the plasma of LA-NPC patients. Based on feedback from IC outcomes, 463 DEPs were identified in the pre-IC plasma between responders and non-responders. A total of 1212 DEPs represented the proteomic changes before and after IC in responders, while 276 DEPs were identified in post-IC plasma between responders and non-responders. WGCNA identified nine protein co-expression modules correlated with clinical traits. Soft cluster analysis identified four IC benefits-related protein clusters. Functional enrichment analysis showed that these proteins may play a role in IC via immunity, complement, coagulation, glycosaminoglycan and serine. Four proteins differentially expressed in all group comparisons, paraoxonase/arylesterase 1 (PON1), insulin-like growth factor-binding protein 3 (IGFBP-3), rheumatoid factor D5 light chain (v-kappa-3) and RNA helicase (DDX55), were associated with clinical traits or IC benefits. A four-protein model accurately identified potential IC beneficiaries (AUC=0.95) while diagnosing LA-NPC (AUC=0.92), and the prediction performance was verified using the models to confirm the effective IC (AUC=0.97) and evaluate IC outcome (AUC=0.94)., Conclusion: The plasma protein profiles among IC responders and non-responders were different. PON1, IGFBP3, v-kappa-3 and DDX55 could serve as potential biomarkers for early identification of IC beneficiaries for individualised treatment of LA-NPC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Pan, Lai, Situ, Liu, Dai, Liang, Zhou, Lu, Ke, Zhang, Chen and Li.)

Gliomas are the most aggressive and common type of malignant brain tumor, with limited treatment options and a dismal prognosis. Angiogenesis, a hallmarks of cancer, is one of two critical events in the progression of gliomas. Accumulating evidence has demonstrated that in glioma dysregulated molecules like long noncoding RNAs (lncRNAs), are closely linked to tumorigenesis and prognosis. However, the effects of and mechanisms of action of lncRNAs during tumor angiogenesis are poorly understood. The effect of lncRNA RP11-732M18.3 on angiogenesis was elucidated through an intracranial orthotopic glioma model, immunohistochemistry, and an in vitro angiogenesis assay. Co-culture experiments and cell migration assays were performed to investigate the function of lncRNA RP11-732M18.3 in vitro . lncRNA RP11-732M18.3 increased CD31 + microvessel density, and overexpression of lncRNA RP11-732M18.3 resulted in poor mouse survival. lncRNA RP11-732M18.3 promoted endothelial cell migration and tube formation. Nomogram and Kaplan-Meier survival analyses indicated that higher VEGFA is correlated with a poor prognosis. Mechanistically, lncRNA RP11-732M18.3 promotes angiogenesis by increasing the nuclear level of EP300 and facilitating the transcription and secretion of VEGFA. Our study contributes to the latest understanding of glioma angiogenesis and prognosis. lncRNA RP11-732M18.3 may be a potential treatment target in glioma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kang, Zhao, Yuan, Liao, Yu, Li, Jin, Cao, Chen, Jin, Chen, Ke, Li, Huang, Hu and Huang.)

This study was aimed to explore the change characteristics of cell differentiation antigen (CD) on bone marrow (BM) granulocytes in patients,with megaloblastic anemia (MA). In combination with BM cell morphology, hemogram, level of blood serum folic acid, level of Vit B(12), cell genetics and biological examination data, the BM granulocytes differentiation antigens in 13 patients with MA were detected by flow cyto metry and analyzed retrospectively, in order to summarize the variation characteristics of CD13, CD33 and CD15 expressed on myeloid cells in patient with MA, including forward scatter light (FSC) and side scatter light (SSC) signal intensity, then these findings were compared with that in normal healthy persons. The results showed that the expression rates of CD13, CD15 and CD33 on granulocytic in patients with MA and normal healthy persons were (44.53 ± 16)%, (96.16 ± 2.67)%, (80.81 ± 14.71)% and (62.33 ± 11.02)%, (99.53 ± 0.46)%, (70.00 ± 7.81)% respectively, in which the expression rate of CD13 and CD15 in patients with MA decreased (P < 0.01), while the expression rate of CD33 increased (P < 0.01). The mean fluorescence intensity (MFI) of CD13, CD15, CD33, SSC and FSC in MA patients and normal healthy persons were 3.39 ± 1.41, 14.29 ± 6.59, 1.95 ± 0.94, 478.78 ± 70.43, 633.46 ± 75.53 and 5.12 ± 1.15, 20.67 ± 5.13, 1.04 ± 0.17, 332.00 ± 38.16, 537.00 ± 16.70 respectively, in which the MFI of CD13 and CD15 on granulocytes in MA patients decreased (P < 0.01),while the MFI of FSC,SSC and CD33 increased (P < 0.01 and P < 0.05). It is concluded that not only the morphology of BM granulocytes in patents with MA shows dysmaturity, but the expressing feature of differentiation antigens on BM granulocytes in MA patients also displays dysmaturity.These findings will contribute to the clinical diagnosis of MA patients.

Objective: To evaluate the effects of levonorgestrel-releasing intrauterine system (LNG-IUS) combined with GnRH analogue (GnRH-a) in the treatment of adenomyosis with uterine body enlargement., Methods: Twelve women (mane age 40.3 years) with adenomyosis and uterine cavity depth over 11 cm received injections of GnRH-a every 4 weeks, and after the uterine cavity depth was reduced to below 10 cm, LNG-IUS was deployed. VAS pain score, PBAC bleeding score, uterine volume, and hemoglobin levels of the women were measured before the treatment and at 6 and 12 months after LNG-IUS placement., Results: The VAS pain score was significantly lowered at 6 and 12 month after LNG-IUS placement (P<0.05), and the PBAC bleeding score also showed significant reductions (P<0.05). The uterine volume decreased significantly at 6 and 12 months after LNG-IUS placement as compared with that before the treatment, but was significantly greater at 6 month in comparison with that at the time of LNG-IUS placement (P<0.05). Serum hemoglobin levels underwent significant increments after LNG-IUS placement (P<0.05)., Conclusion: LNG-IUS combined with GnRH analogue injection can be effective in the treatment of adenomyosis with dysmenorrhea and hypermenorrhea.

Objective: To evaluate the performance of BNII auto-analyzer system in detecting C3 and C4., Methods: CLSI protocols (EP15-A, EP6-A, EP9-A2) and other relevant literatures were use to or evaluate the precision, accuracy, linearity of C3 and C4 detection by the auto-analyzer system, and the results were compared with the recognized standards., Results: The relative bias of C3 and C4 was less than one third of the CLIA'88 standard and the precision met the clinical requirement. The results tested by DADE BNII system were not compatible with those by Roche Modular System. C3 showed good linearity in the tests (R2>0.975, P<0.05) with a linearity range of 0.18-5.1 g/L. The linearity of C4 was not available because of lack of high-level samples., Conclusion: The performances of DADE BNII System basically meet the recognized standards in clinical detection of C3 and C4, but the method comparison needs further validation.

Background & Objective: Endometrial carcinoma is a common malignant tumor of female reproductive system, with an increasing incidence in China. Adenomatous polyposis coli (APC) gene, a tumor suppressor gene, is expressed in many tissues, and has a certain relationship with ovarian cancer. This study was to observe the expression and DNA methylation of APC gene in endometrioid adenocarcinoma, and explore its correlations to the occurrence and development of this disease., Methods: The methylation, mRNA and protein expression of APC gene were detected by methylation-specific polymerase chain reaction (PCR), reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry in 30 specimens of normal proliferative endometrium, 30 specimens of atypical hyperplastic endometrium and 60 specimens of endometrioid adenocarcinoma., Results: The methylation rate of APC gene was significantly higher, the positive rates of APC mRNA and protein were significantly lower in endometrioid adenocarcinoma than in atypical hyperplastic endometrium and normal proliferative endometrium (65.0% vs. 33.3% and 23.3%, 33.3% vs. 63.3% and 73.3%, 30.0% vs. 50.0% and 66.7%,P<0.05). There was no significant difference between atypical hyperplastic endometrium and normal endometrium (P>0.05). APC methylation was positively correlated to APC mRNA expression., Conclusion: The expression and DNA methylation of APC gene are certainly related with the occurrence and development of endometrioid adenocarcinoma.