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Background and Aim: Even though the role of D2 (ergocalciferol) on cardiovascular disease risk components has been studied, conflicting results have been reported. Moreover, no single study has studied all these parameters and the role of vitamin D2 individually has not been assessed; hence, this systematic review and meta-analysis of randomized controlled trials was conducted to assess the effect of vitamin D2 supplementation on lipid profile, anthropometric indices, blood pressure, and inflammatory and glycemic biomarkers in humans., Methods: Web of Science, Scopus, PubMed/Medline, and Embase were searched from database inception to July 2024, and the random effects model, according to the DerSimonian and Laird method, was used to generate combined estimates of the intervention's effect on the outcomes., Results: After full-text analysis, 11 eligible articles were included in our meta-analyses. No statistically significant association was observed between vitamin D2 administration and BMI, WC, TC, HDL-C, LDL-C, TG, DBP or SBP; however, a statistically significant decrease in CRP (WMD: - 1.92 mg/dL, 95 % CI: - 3.30 to - 0.54, P = 0.006) and HbA1c levels (WMD: - 0.37 %, 95 % CI: - 0.66 to - 0.09, P = 0.009), and a non-statistically significant decrease in FBG (WMD: - 4.61 mg/dL, 95 % CI: - 14.71 to 5.47, P = 0.370, I2 = 90 %, P ˂ 0.001) and HOMA-IR (WMD: - 0.10, 95 % CI: - 0.17-0.03, P = 0.002) were detected., Conclusion: In summary, our systematic review and meta-analysis discovered that vitamin D2 administration was associated with a statistically significant decrease in CRP and HbA1c levels, without a significant correlation with other outcomes., Competing Interests: Conflict of interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

PDIA5 is responsible for modification of disulfide bonds of proteins. However, its impact on the malignant progression of glioblastoma multiforme (GBM) remains unknown. We analyzed the expression and prognostic significance of PDIA5 in cohorts of GBM and clinical samples. The PDIA5 protein was significantly overexpressed in GBM tissues, and higher expression of PDIA5 was statistically associated with a worse prognosis in patients with GBM. Transcriptional data from PDIA5 knockdown GBM cells revealed that downstream regulatory genes of PDIA5 were enriched in malignant regulatory pathways and PDIA5 enhanced the proliferative and invasive abilities of GBM cells. By constructing a PDIA5 CXXC motif mutant plasmid, we found CCAR1 was the vital downstream factor of PDIA5 in regulating GBM malignancy in vitro and in vivo . Additionally, RUNX1 bound to the promoter region of PDIA5 and regulated gene transcription, leading to activation of the PDIA5/CCAR1 regulatory axis in GBM. The RUNX1/PDIA5/CCAR1 axis significantly influenced the malignant behavior of GBM cells. In conclusion, this study comprehensively elucidates the crucial role of PDIA5 in the malignant progression of GBM. Downregulating PDIA5 can mitigate the malignant biological behavior of GBM both in vitro and in vivo , potentially improving the efficacy of treatment for clinical patients with GBM., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Rationale: Since oncogene expression products often exhibit upregulation or abnormally activated activity, developing a technique to regulate abnormal protein levels represent a viable approach for treating tumors and protein abnormality-related diseases. Methods: We first screened out eMIATAC components with high targeted degradation efficiency and explored the mechanism by which eMIATAC induced target protein degradation, and verified the degradation efficiency of the target protein by protein imprinting and flow cytometry. Next, we recombined eMIATAC with some controllable elements to verify the regulatable degradation performance of the target protein. Subsequently, we constructed eMIATAC that can express targeted degradation of AKT1 and verified its effect on GBM cell development in vitro and in vivo. Finally, we concatenated eMIATAC with CAR sequences to construct CAR-T cells with low BATF protein levels and verified the changes in their anti-tumor efficacy. Results: we developed a system based on the endosome-microautophagy-lysosome pathway for degrading endogenous proteins: endosome-MicroAutophagy TArgeting Chimera (eMIATAC), dependent on Vps4A instead of lysosomal-associated membrane protein 2A (LAMP2A) to bind to the chaperone Hsc70 and the protein of interest (POI). The complex was then transported to the lysosome by late endosomes, where degradation occurred similarly to microautophagy. The eMIATACs demonstrated accuracy, efficiency, reversibility, and controllability in degrading the target protein EGFP. Moreover, eMIATAC exhibited excellent performance in knocking down POI when targeting endogenous proteins in vivo and in vitro. Conclusions: The eMIATACs could not only directly knock down abnormal proteins for glioma treatment but also enhance the therapeutic effect of CAR-T cell therapy for tumors by knocking down T cell exhaustion-related proteins. The newly developed eMIATAC system holds promise as a novel tool for protein knockdown strategies. By enabling direct control over endogenous protein levels, eMIATAC has the potential to revolutionize treatment for cancer and genetic diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Studies have shown that a lot of traditional Chinese medicines could improve the immunity of the body. Dangdi oral liquid (DDO) was mainly composed of Angelica sinensis (Oliv.) Diels (Danggui), Rehmannia glutinosa Libosch. (Dihuang), Achyranthes bidentata Bl. (Niuxi), Glycyrrhiza uralensis Fisch. (Gancao). In this study, the rapid ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) method was used to identify the potentially effective compounds of DDO. Then the immune activity of DDO was measured by lymphocyte proliferation, macrophage phagocytic function, NK cell activity, delayed type hypersensitivity reaction, hemolytic plaque number, sIgA content and immune organ index. The results showed that a total of 51 compounds were identified. In addition, DDO could significantly promote the lymphocyte proliferation, improve macrophage phagocytic ability, NK cell activity, hemolytic plaque number, sIgA content and immune organ index compared with control group, and the medium dose possessed the best efficacy (P＜0.05). These results indicated that DDO could enhance the immunity of mice., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interestsZhihong Zhou reports financial support was provided by 10.13039/501100004735Hunan Provincial Natural Science Foundation of China. Zhihong Zhou reports financial support was provided by Scientific Research Project of Hunan Provincial Health Commission. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Smart theranostic nanoprobes with the integration of multiple therapeutic modalities are preferred for precise diagnosis and efficient therapy of tumors. However, it remains a big challenge to arrange the imaging and two or more kinds of therapeutic agents without weakening the intended performances. In addition, most existing fluorescence (FL) imaging agents suffer from low spatiotemporal resolution due to the short emission wavelength (<900 nm). Here, novel three-in-one Ag 2 S quantum dot (QD)-based smart theranostic nanoprobes were proposed for in situ ratiometric NIR-II FL imaging-guided ion/gas combination therapy of tumors. Under the acidic tumor microenvironment, three-in-one Ag 2 S QDs underwent destructive degradation, generating toxic Ag + and H 2 S. Meanwhile, their FL emission at 1270 nm was weakened. Upon introduction of a downconversion nanoparticle (DCNP) as the delivery carrier and NIR-II FL reference signal unit, the formed Ag 2 S QD-based theranostic nanoprobes could achieve precise diagnosis of tumors through ratiometric NIR-II FL signals. Also, the generated Ag + and H 2 S enabled specific ion/gas combination therapy toward tumors. By combining the imaging and therapeutic functions, three-in-one Ag 2 S QDs may open a simple yet reliable avenue to design theranostic nanoprobes.

Antibiotics are causing widespread concern as one of the emerging contaminants. There is the abuse of antibiotics in high-density open aquaculture, and the tailwater is often discharged into surrounding rivers. At the same time, the water replenishment of open aquaculture ponds from nearby rivers containing antibiotic contamination from different sources may result in cross-contamination. However, it is still unclear which pollution intensity is greater in rivers or in open aquaculture. So in this paper, the levels of 20 antibiotics (i.e., Fluoroquinolones (FQs), Sulfonamides (SAs), Tetracyclines (TCs), Macrolides (MLs) and Lincosamides (LCs)) in rivers and high-density open aquaculture ponds were investigated in the Baini River basin in the suburbs of Guangzhou, China. The results showed that norfloxacin (NFX) was the predominant antibiotic in river and aquaculture water, with concentrations ranging from 6.12 to 156.04 ng/L and from 7.47 to 82.62 ng/L in both aquatic systems, respectively. As for the pollution intensity of antibiotics, the annual pollution contribution (28.64 kg/a) of the river water supply to open aquaculture is higher than that (10.81 kg/a) of open aquaculture to the river, which means river pollution has a greater impact on aquaculture ponds. The risk quotient (RQ) showed that the ecological risk of lincomycin (LIN), erythromycin (ERY), sulfamethoxazole (SMX), norfloxacin (NFX), ciprofloxacin (CFX) and chlortetracycline (CTC) in rivers and aquaculture environments had high ecological risks from 1.21 to 1.81. Water interactions with contaminated rivers will result in a corresponding increase in the ecological risk of antibiotics in the aquaculture environment. Overall, according to the results, the risk of polluted rivers to open aquaculture cannot be ignored, and it is recommended that open aquaculture should use these water sources with caution, and that the water quality evaluation of aquaculture water should be increased with monitoring indicators for emerging contaminants such as antibiotics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Hybrid constructed wetlands (HCWs) are a promising solution for water ecology and environmental treatment, not only for conventional types of water pollution but also for antibiotics. Among the critical parameters for wetlands, the hydraulic loading rate (HLR) is especially important given the challenges of antibiotics treatment and frequent extreme rainfall. To investigate the removal performance of different HLRs on nutrients and antibiotics, as well as the response of antibiotics to nutrient removal, and the impact of HLRs on microbial communities, new HCWs with vertical flow constructed wetlands (VFCWs) and floating constructed wetlands (FCWs) in series were built. The results of the study showed that: (1) HCWs are highly effective in removing chemical oxygen demand (COD), NH 4 + -N, NO 2 - -N, and total phosphorus (TP) at low HLR (L&#95;HLR), with removal efficiencies as high as 97.8%, 99.6%, 100%, and 80.5%. However, high HLR (H&#95;HLR) reduced their removal efficiencies; (2) The average removal efficiency of fluoroquinolones (FQs) under different HLRs was consistently high, at 99.9%, while the average removal efficiency of macrolides (MLs) was 96.3% (L&#95;HLR) and 88.4% (H&#95;HLR). The removal efficiency of sulfonamides (SAs) was susceptible to HLRs, and the removal of antibiotics occurred mainly in the rhizosphere zone of wetland; (3) High concentrations of antibiotics in HCWs were found to inhibit and poison plant growth and to reduce the removal efficiency of TP by 12%. However, they had a minor effect on the removal efficiency of carbon and nitrogen nutrients; (4) H&#95;HLR altered the diversity and abundance of microbial communities in different compartments of the wetland and also reduced the relative abundance of Bacillus, Hydrogenophaga, Nakamurella, Denitratisoma and Acidovorax genera, which are involved in denitrification and phosphorus removal processes. This alteration in microbial communities was one of the main reasons for the reduced performance of nitrogen and phosphorus removal., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

By integrating near-infrared (NIR) light-dependent optical control and DNA walkers-based signal amplification, upconversion luminescence-activated DNA nanomachines hold great potential in conducting an in vivo analysis. For the typical DNA nanomachines, the immobile multivalent recognition interface greatly compromised the reaction kinetics and amplification efficiency due to the cleavage-dependent response mode. In this work, novel upconversion luminescence-activated DNA nanomachines with a fluid multivalent recognition interface were reported for rapid and sensitive in vivo imaging. As a proof-of-concept study, the photolocked DNAzyme-based walker system was anchored on the surface of phospholipid membrane-coated upconversion nanoparticles through the cholesterol-phospholipid interaction to acquire a fluid multivalent recognition interface. Upon sequential inputs of NIR light and metal ions, the formed DNA nanomachines were autonomously initiated and generated a cascade of amplified signal. Relative to the typical DNA nanomachines, the proposed ones possess an accelerated reaction rate and an improved amplification capability owing to a higher local concentration by the lateral mobility. The present work provides a versatile alternative for performing precise and highly efficient in vivo analysis.

The seco-prezizaane-type sesquiterpenes (SPS), as a special class of sesquiterpenes with a highly oxidative five-ring cage structure and seven consecutive chiral centers, are isolated from the genus Illicium , which have a variety of biological activities, including neurotoxicity and neurotrophic effects, etc. This review summarizes the chemical constituents and pharmacological effects of SPS, and discusses the potential trend and scope of future research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.)

Introduction: Asthma is a common chronic condition in children. Several studies have explored the potential association between IL10 rs1800896 polymorphism and the risk of asthma in children, but the findings have been inconsistent. To address these discrepancies, we conducted a systematic review and meta-analysis to assess the relationship between IL10 rs1800896 polymorphisms and the susceptibility to pediatric asthma., Methods: A literature search was conducted in PubMed, Scopus, Web of Science, and CNKI databases to identify eligible studies through April 2022. Meta-analysis was then performed using five genetic models: dominant, recessive, homozygous, heterozygous, and allele., Results: A total of 12 studies comprising 1645 cases along with 1447 controls were included in this meta-analysis. It was found that rs1800896 was not associated significantly with susceptibility to childhood asthma in all genetic models investigated. Subgroup analysis based on the ethnic background of the subjects revealed that rs1800896 was significantly linked to a lower risk of pediatric asthma among Asians in the homozygous model (OR = 0.311, 95% CI = 0.152-0.637, P = 0.001) and in the recessive model (OR = 0.585, 95% CI = 0.405-0.846, P = 0.004), whereas no significant relationship was observed in Egyptians (P > 0.05)., Conclusion: In conclusion, IL10 rs1800896 polymorphism may be useful as a predictive marker for childhood asthma in Asians, although further studies are needed to validate the study results., (© 2023 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Formation of nitrogenous disinfection byproducts from aliphatic amines is a widespread concern owing to the serious health risks associated with them. However, the mechanisms of transforming aliphatic amines and forming nitro products in the UV/chlorine process have rarely been discussed, which are investigated in this work. Initially, secondary amines (R 1 R 2 NH) are transformed into secondary organic chloramines (R 1 R 2 NCl) via chlorination. Subsequently, radicals, such as HO• and Cl•, are found to contribute predominantly to such transformations. The rate constants at which HO•, Cl•, and Cl 2 •- react with R 1 R 2 NCl are (2.4-5.1) × 10 9 , (1.5-3.8) × 10 9 , and (1.2-6.1) × 10 7 M -1 s -1 , respectively. Consequently, R 1 R 2 NCl are transformed into primary amines (R 1 NH 2 /R 2 NH 2 ) and chlorinated primary amines (R 1 NHCl/R 2 NHCl and R 1 NCl 2 /R 2 NCl 2 ) by excess chlorine. Furthermore, primarily driven by UV photolysis, chlorinated primary amines can be transformed into nitroalkanes with conversion rates of ∼10%. Dissolved oxygen and free chlorine play crucial roles in forming nitroalkanes, and post-chlorination can further form chloronitroalkanes, such as trichloronitromethane (TCNM). Radicals are involved in forming TCNM in the UV/chlorine process. This study provides new insights into the mechanisms of transforming aliphatic amines and forming nitro products using the UV/chlorine process.

Epilepsy is a common neurological disorder in children. Numerous studies have demonstrated the association between SCN1A polymorphisms and risk of epilepsy in adults, but their role in epilepsy in children has just gained traction and results have remained inconsistent. In this work, we performed a systematic review and meta-analysis to assess the association between SCN1A polymorphisms and risk for epilepsy in children. A systematic literature search was performed in PubMed, Scopus, Web of Science, China National Knowledge Internet, Wanfang and VIP databases to identify eligible studies up to June 2023. Quantitative data synthesis was then performed under five genetic models: dominant, recessive, homozygous, heterozygous, and allele. Five studies involving 1380 subjects were included in the meta-analysis. Among many SCN1A polymorphisms reported, only rs2298771 was repeatedly studied in these reports. Pooled analysis demonstrated that there was no significant association between the polymorphism and risk of epilepsy in children (P>0.05). In conclusion, SCN1A rs2298771 polymorphism was not significantly associated with the risk of epilepsy in children., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Ltd.)

Chondrocyte survival is critical for the preservation of a healthy cartilage matrix. Limited chondrocyte function and survival can result in articular cartilage failure, thereby contributing to osteoarthritis (OA). In this study, miR-5581 was significantly up-regulated in OA samples, and miR-5581-associated genes were enriched in Kras signaling. miR-5581 up-regulation was observed in clinical OA samples and IL-1β-stimulated chondrocytes. miR-5581 inhibition attenuated IL-1β-induced chondrocyte proliferation suppression, extracellular matrix (ECM) synthesis suppression and degradation, and IL-1β-suppressed Kras signaling activation. miR-5581 was targeted to inhibit NRF1. In IL-1β-treated chondrocytes, NRF1 overexpression attenuated IL-1β-induced cellular damage and partially abolished the effects of miR-5581 overexpression on IL-1β-stimulated chondrocytes. NRF1 was down-regulated in knee joint cartilage of OA mice. In conclusion, miR-5581, which was up-regulated in OA samples and IL-1β-stimulated chondrocytes, inhibited chondrocyte proliferation and ECM synthesis, and promoted ECM degradation through targeting NRF1, whereby Kras signaling might be involved., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: Swertiamarin (STM) belongs to iridoid class of compounds, and the heat-transformed products (HTPS) are produced by STM in the process of drug processing. The purpose of this study was to explore the protective effect and mechanism of STM or HTPS on acetaminophen (APAP)-induced hepatotoxicity., Methods: Mice and L-O2 cells were given APAP to establish the hepatotoxicity model in vivo and in vitro . The effects of STM or HTPS on oxidative stress, inflammation, and apoptosis induced by APAP were evaluated, with N-acetylcysteine (NAC) as a positive control., Results: STM or HTPS reduced the APAP-induced apoptosis of L-O2 cells and significantly alleviated the liver injury index induced by APAP ( p  < 0.01, 0.005) Interestingly, HTPS had better protective effect against APAP-induced hepatotoxicity than STM (p < 0.05). In addition STM or HTPS improved the histological abnormalities; inhibited lipid peroxidation and reduced the level of inflammatory mediators. They also activated the defense system of nuclear factor erythroid 2 related factor 2 (Nrf-2) and inhibited nuclear factor-κ B (NF- κ B)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Ice adhesion is important when designing aircraft anti-icing/de-icing systems. Major and minor grooves are common in the skin of aircraft. However, the effects of millimeter-scale grooves on ice adhesive strength have not been given due attention. Specimens with varying depths, widths, and numbers of grooves were fabricated by machining to investigate the ice adhesive characteristics of large-sized grooved aluminum surfaces. After the ice cube was frozen on the surface using a silicon mold, the adhesive force was measured using a self-assembled shear adhesive force setup. A correlation between groove size and apparent adhesive strength in the perpendicular loading direction was established based on the experimental results. Every 1% increase in the groove width ratio was associated with an 18.7 kPa increase in apparent adhesive strength. The increasing speed of the adhesion rapidly decayed as the groove depth increased. The increase in adhesion reached 99% of the maximum increase when the groove depth reached 0.8 times the width. The number of grooves had little effect on the adhesion when the total width of the grooves was kept constant. Stress distribution analysis was conducted using the finite element method, and the results were in accordance with the cracking phenomena in the experiments. The adhesive strength in the parallel loading direction was 30% lower than that in the perpendicular loading direction for all six chosen surfaces. This study is the first to propose a quantitative relationship between the surface textures of millimeter-sized grooves and ice adhesive strength. The loading orientation also had a substantial influence on adhesion. The results will serve as a valuable reference for future studies on ice adhesion on textured surfaces and for improving the performance of anti-icing/de-icing systems.

Purpose: The DIALIZE China study (Reduce Incidence of Pre-Dialysis Hyperkalaemia With Sodium Zirconium Cyclosilicate in Chinese Subjects) (NCT04217590) evaluated sodium zirconium cyclosilicate (SZC) for the management of hyperkalemia in Chinese patients undergoing hemodialysis., Methods: In the double-blind, Phase IIIb DIALIZE China study, Chinese adults with kidney failure and predialysis hyperkalemia (predialysis serum potassium [sK + ] concentration >5.4 mmol/L after the long interdialytic interval [LIDI] and >5.0 mmol/L after ≥1 short interdialytic interval) who were receiving hemodialysis 3 times weekly were randomized to placebo or SZC 5 g once daily on nondialysis days. Doses were titrated towards maintaining normokalemia for 4 weeks (titration period) in 5-g increments up to 15 g. Primary efficacy was the proportion of responders during the 4-week evaluation period following the titration period (ie, those with a predialysis sK + of 4.0-5.0 mmol/L for at least 3 of 4 hemodialysis visits following the LIDI) who did not require urgent rescue therapy., Findings: Overall, 134 adults (mean [SD] age, 55 [11.3] years) were randomized to SZC or placebo (n = 67 each). There were significantly more responders with SZC (37.3%) versus placebo (10.4%; estimated odds ratio [OR] = 5.10; 95% CI, 1.90-15.12; P < 0.001). The probability of all predialysis sK + concentrations being 3.5 to 5.5 mmol/L was significantly higher with SZC versus placebo (estimated OR = 6.41; 95% CI, 2.71-15.12; P < 0.001). A greater proportion of patients achieved an sK + of 3.5 to 5.5 mmol/L on at least 3 of 4 LIDI visits during evaluation with SZC (73.1%) versus placebo (29.9%). Serious adverse events occurred in 9.1% and 11.9% of patients in the SZC and placebo groups, respectively., Implications: SZC treatment for predialysis hyperkalemia is effective and well tolerated in Chinese patients with kidney failure receiving hemodialysis., Clinicaltrials: gov identifier: NCT04217590., Competing Interests: Declaration of Competing Interest Xiangwen Meng, Zhiren Chang, June Zhao, Peter Wessman, and Peng Xiang are employees of, and hold or may hold stock in, AstraZeneca. Zhaohui Ni, Chaosheng Chen, and Xinzhou Zhang declare grant support from AstraZeneca, and Yi Li declares grant and educational event support from AstraZeneca. The authors have indicated that they have no other conflicts of interest regarding the content of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated potent clinical efficacy in the treatment of hematopoietic malignancies. However, the application of CAR-T in solid tumors has been limited due in part to the expression of inhibitory molecules in the tumor microenvironment, leading to T-cell exhaustion. To overcome this limitation, we have developed a synthetic T-cell receptor (TCR) that targets programmed death-ligand 1 (PD-L1), a molecule that is widely expressed in various solid tumors and plays a pivotal role in T-cell exhaustion. Our novel TCR platform is based on antibody-based binding domain, which is typically a single-chain variable fragment (scFv), fused to the γδ TCRs (TCRγδ). We have utilized the T-cell receptor alpha constant (TRAC) locus editing approach to express cell surface scFv of anti-PD-L1, which is fused to the constant region of the TCRγ or TCRδ chain in activated T cells derived from peripheral blood mononuclear cells (PBMCs). Our results indicate that these reconfigured receptors, both γ-TCRγδ and δ-TCRγδ, have the capability to transduce signals, produce inflammatory cytokines, degranulate and exert tumor killing activity upon engagement with PD-L1 antigen in vitro. Additionally, we have also shown that γ-TCRγδ exerted superior efficacy than δ-TCRγδ in in vivo xenograft model., (© 2023. The Author(s).)

Hyperuricemia is the result of overproduction and/or underexcretion of uric acid, and it is a well-known risk factor for gout, hypertension, and diabetes. However, available drugs for hyperuricemia in the clinic are limited. Recently, a lot of research has been conducted in order to discover new uric acid-lowering agents from plants and foods. We found that the extracts from the pericarp of mangosteen reduced urate. Bioactivity-guided study showed that α-mangostin was the principal constituent. Herein, we reported for the first time the hypouricemic activities and underling mechanism of α-mangostin. The α-mangostin dose- and time-dependently decreased the levels of serum urate in hyperuricemic mice and markedly increased the clearance of urate in hyperuricemic rats, exhibiting a promotion of urate excretion in the kidney. Further evidence showed that α-mangostin significantly decreased the protein levels of GLUT9 in the kidneys. The change in the expression of URAT1 was not observed. Moreover, α-mangostin did not inhibit the activities of xanthine oxidoreductase and uricase in vitro or in vivo . Taken together, these findings suggest that α-mangostin has potential to be developed as a new anti-hyperuricemic agent with promoting uric acid excretion.

Context: Bushen Yiyuan recipe (BYR) is an effective Chinese prescription with antifatigue and antioxidation effects., Objective: The effects of BYR on testosterone synthesis in rat Leydig cells with exercise-induced low serum testosterone levels (EILST) are assessed., Materials and Methods: Thirty-two Sprague-Dawley rats were chronically trained for 6 weeks to establish an EILST model. EILST rats were divided into model (physiological saline), EFE (700 mg/kg ethanol extract of Epimedii folium , the dried leaves of Epimedium brevicornu Maxim [Berberidaceae]), and BYR groups (350 and 700 mg/kg) for 6 weeks. Expression of HMG-CoA, LDL-R, SR-BI, STAR and CYP11A1 were quantified by RT qPCR and Western blots., Results: Compared with the model group (115.52 ± 13.05 μg/dL; 67.83 ± 14.29; 0.32 ± 0.04; 0.33 ± 0.02; 0.38 ± 0.01), serum testosterone, testosterone/cortisol ratio, HMG-CoA, STAR and CYP11A1 relative protein expression significantly increased in low-dose BYR (210.60 ± 5.08 μg/dL; 119.38 ± 13.02; 0.47 ± 0.01; 0.46 ± 0.03; 0.46 ± 0.02), high-dose BYR (220.57 ± 14.71 μg/dL; 124.26 ± 14.79; 0.49 ± 0.02; 0.42 ± 0.03; 0.51 ± 0.02), and EFE groups (206.83 ± 5.54 μg/dL; 119.53 ± 25.04; 0.45 ± 0.02; 0.42 ± 0.02; 0.41 ± 0.02) (all p  < 0.01, except for CYP11A1 in EFE group). HMG-CoA, STAR and CYP11A1 mRNA relative expression significantly increased in low-dose and high-dose BYR group compared to model group (all p  < 0.01)., Conclusions: BYR affects endogenous cholesterol synthesis and testosterone synthesis to prevent and treat EILST levels in rats. It can improve the body's sports ability.

Maprotiline is an antidepressant that has been found to cause hypoglycemia. However, the effect of maprotiline on diabetic nephropathy (DN) has not been investigated. Here, we explored the effect of maprotiline on human renal glomerular endothelial cells (HRGECs) in response to high glucose (HG) stimulation. We found that maprotiline attenuated HG-induced oxidative stress in HRGECs with decreased reactive oxygen species production and increased superoxide dismutase activity. Maprotiline repressed the HG-induced expression of cyclooxygenases 2 at both mRNA and protein levels in HRGECs. The increased thromboxane B2 level and decreased 6-keto-prostaglandin F1α level induced by HG were significantly attenuated by maprotiline treatment. Maprotiline also prevented the HG-induced increase in the permeability of HRGECs and the decrease in the zonula occludens-1 expression and downregulated HG-induced increase in the expression of protein kinase C-α (PKC-α) in HRGECs. This protective effect of maprotiline on HG-induced HRGECs dysfunction was abolished by overexpression of PKC-α. In conclusion, maprotiline displayed a protective effect on HG-challenged HRGECs, which was mediated by the regulation of PKC-α. These findings provide further evidence for the potential use of maprotiline for the treatment of DN., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The formation of disinfection byproducts (DBPs) during UV/chlorine treatment, especially nitrogenous DBPs, is not well understood. This study investigated the formation mechanisms for dichloroacetonitrile (DCAN) from typical amino compounds during UV/chlorine treatment. Compared to chlorination, the yields of DCAN increase by 88-240% during UV/chlorine treatment from real waters, while the yields of DCAN from amino compounds increase by 3.3-5724 times. Amino compounds with electron-withdrawing side chains show much higher DCAN formation than those with electron-donating side chains. Phenylethylamine, l- phenylalanine, and l-phenylalanyl-l-phenylalanine were selected to represent amines, amino acids, and peptides, respectively, to investigate the formation pathways for DCAN during UV/chlorine treatment. First, chlorination of amines, amino acids, and peptides rapidly forms N -chloramines via chlorine substitution. Then, UV photolysis but not radicals promotes the transformation from N -chloramines to N -chloroaldimines and then to phenylacetonitrile, with yields of 5.4, 51.0, and 19.8% from chlorinated phenylethylamine, l-phenylalanine, and l-phenylalanyl-l-phenylalanine to phenylacetonitrile, respectively. Finally, phenylacetonitrile is transformed to DCAN with conversion ratios of 14.2-25.6%, which is attributed to radical oxidation, as indicated by scavenging experiments and density functional theory calculations. This study elucidates the pathways and mechanisms for DCAN formation from typical amino compounds during UV/chlorine treatment.

Long noncoding RNAs (lncRNAs) and miRNAs have been reported to participate in intervertebral disc degeneration (IDD) progression. However, the key lncRNA-miRNA axis and its corresponding affected hub genes in IDD remain unknown. In this study, weighted gene coexpression network analysis (WGCNA) was first used to determine the key gene cluster and hub genes implicated in IDD progression. The expression levels of ADIRF-AS1, miR-214-3p, and SERPINA1 in nucleus pulposus (NP) tissues were detected. The ADIRF-AS1/miR-214-3p/SERPINA1 axis was identified, and its effects on the proliferation, senescence, and apoptosis of NP cells were investigated in vitro and in vivo. SERPINA1 overexpression in NP cells promoted cell viability and inhibited cell apoptosis and senescence. Moreover, SERPINA1 regulated the IDD grade in rat models. The lncRNA ADIRF-AS1 was downregulated in high-grade degeneration NP tissues and positively correlated with SERPINA1. ADIRF-AS1 overexpression attenuated cellular degenerative changes in NP cells. miR-214-3p directly bound to SERPINA1 and ADIRF-AS1 and negatively regulated ADIRF-AS1 expression. miR-214-3p inhibition exerted similar effects on cellular degenerative changes in NP cells to SERPINA1 or ADIRF-AS1 overexpression. Furthermore, miR-214-3p overexpression partially reversed the effects of ADIRF-AS1 overexpression. Collectively, these data suggest that ADIRF-AS1 overexpression could mitigate IDD by binding to miR-214-3p to upregulate SERPINA1. Additional studies (especially those using an axial loading-induced IDD animal model) will be needed to further validate the role of the ADIRF-AS1/miR-214-3p/SERPINA1 signaling axis in IDD progression., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical effect of Mudan granule on peripheral neuritis caused by chronic renal insufficiency (CRI)., Methods: Sixty patients with peripheral neuritis caused by CRI treated in our hospital were included from February 2018 to April 2021 in this study. The patients were arbitrarily assigned into control group and study group. The former accepted routine treatment, while the latter accepted Mudan granule treatment. The clinical efficacy, traditional Chinese medicine (TCM) clinical symptom score, nerve conduction velocity, hemorheology index, renal function index, and inflammatory factor index were compared., Results: We firstly compared the clinical efficacy: the study group was clinically cured in 22 cases, obviously effective in 5 cases, effective in 3 cases, and ineffective in 1 case, with a total effective rate of 96.67%. The control group was clinically cured in 9 cases, obviously effective in 8 cases, effective in 7 cases, and ineffective in 6 cases, with a total effective rate of 80.00%. The total effective rate of the study group was higher compared to the control group ( P < 0.05). Secondly, we compared the TCM clinical symptom scores; before treatment, there exhibited no significant difference ( P > 0.05); after treatment, the TCM clinical symptom scores decreased. The clinical symptom score of TCM in the study group was lower compared to the control group ( P < 0.05). Compared with the control group, the nerve conduction velocity of left MCV, right MCV, left SCV, and right SCV in the study group were remarkably higher. In terms of the hemorheological indexes, the high-shear whole blood viscosity, low-shear whole blood viscosity, and plasma viscosity in the study group were lower compared with the control group ( P < 0.05). Before treatment, there existed no significant difference in renal function indexes, but after treatment, the renal function indexes decreased, and the levels of serum creatinine (SCr), blood urea nitrogen (BUN), and uric acid (UA) in the study group were lower compared to the control group ( P < 0.05). Finally, we compared the indexes of inflammatory factors; there existed no significant difference before treatment, but after treatment, the indexes of inflammatory factors decreased in both groups, and the levels of IL-6 and CRP in the study group were lower compared to the control group ( P < 0.05)., Conclusion: For peripheral neuritis caused by CRI, Mudan granule can remarkably promote the clinical symptoms of TCM and reduce the syndrome score of TCM; moreover, it can remarkably increase the nerve conduction velocity of median nerve and common peroneal nerve and reduce blood viscosity, which is worth popularizing and developing in clinic., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Xinle Li et al.)

piRNAs (PIWI-interacting RNAs) are a class of small non-coding RNAs (ncRNAs) abundantly expressed in germline cells and involved in suppressing the transposon activity. Interestingly, recent studies have found piRNA expression in the central nervous system (CNS), yet the underlying biological significance remains largely unknown. In this study, we investigated the expression and function of piRNAs during the retinoic acid (RA)-mediated neuronal differentiation in NT2 cells, a human embryonal carcinoma cell line. We identified a cohort of differentially expressed piRNAs by microarray. Two piRNAs, DQ582359 and DQ596268, were increasingly upregulated during the RA-induced differentiation and involved in regulating the expression of neuronal markers, MAP2 and TUBB3. Furthermore, these piRNAs were found to associate with cold-shock domain (CSD)-containing RNA binding proteins, DIS3, DIS3L2, and YB-1. Markedly, overexpression of these piRNAs further enhanced the protein levels of MAP2 and TUBB3, potentially by downregulating DIS3, DIS3L2, and YB-1. Hence, our study has identified a novel somatic function of piRNAs in regulating neuronal gene expression. The interaction of piRNA with some CSD-containing proteins can be further explored to enhance neuronal differentiation to treat neurodegenerative diseases., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: We aimed to construct a novel epithelial-mesenchymal transition (EMT)-related gene pairs (ERGPs) signature to predict overall survival (OS) in skin cutaneous melanoma (CM) patients., Methods: Expression data of the relevant genes, corresponding clinicopathological parameters, and follow-up data were obtained from The Cancer Genome Atlas database. Univariate Cox regression analysis was utilized to identify ERGPs significantly associated with OS, and LASSO analysis was used to identify the genes used for the construction of the ERGPs signature. The optimal cutoff value determined by the receiver operating characteristic curve was used to classify patients into high-risk and low-risk groups. Survival curves were generated using the Kaplan-Meier method, and differences between the two groups were estimated using the log-rank test. The independent external datasets GSE65904 and GSE19234 were used to verify the performance of the ERGPs signature using the area under the curve (AUC) values. In addition, we also integrated clinicopathological parameters and risk scores to develop a nomogram that can individually predict the prognosis of patients with CM., Results: A total of 104 ERGPs related to OS were obtained, of which 21 ERGPs were selected for the construction of the signature. All CM patients were stratified into high-and low-risk groups based on an optimal risk score cutoff value of 0.281. According to the Kaplan-Meier analysis, the mortality rate in the low-risk group was lower than that in the high-risk group in the TCGA cohort ( P  < 0.001), GSE65904 cohort ( P  = 0.006), and GSE19234 cohort ( P  = 0.002). Multivariate Cox regression analysis indicated that our ERGP signature was an independent risk factor for OS in CM patients in the three cohorts (for TCGA: HR, 2.560; 95% CI [1.907-3.436]; P  < 0.001; for GSE65904: HR = 2.235, 95% CI [1.492-3.347], P  < 0.001; for GSE19234: HR = 2.458, 95% CI [1.065-5.669], P  = 0.035). The AUC value for predicting the 5-year survival rate of patients with CM of our developed model was higher than that of two previously established prognostic signatures. Both the calibration curve and the C-index (0.752, 95% CI [0.678-0.826]) indicated that the developed nomogram was highly accurate. Most importantly, the decision curve analysis results showed that the nomogram had a higher net benefit than that of the American Joint Committee on Cancer stage system., Conclusion: Our study established an ERGPs signature that could be potentially used in a clinical setting as a genetic biomarker for risk stratification of CM patients. In addition, the ERGPs signature could also predict which CM patients will benefit from PD-1 and PD-L1 inhibitors., Competing Interests: The authors declare there are no competing interests., (©2022 Shi et al.)

Objective: To explore the relationship between different degrees of compression and clinical symptoms in patients with the myocardial bridge and the risk factors of proximal atherosclerosis., Methods: The clinical data of 156 patients with the myocardial bridge who underwent selective coronary angiography in our hospital from December 2010 to December 2015 were collected. The patients were divided into Noble grade I group (102 cases) and Noble grades II-III group (54 cases) according to the degree of mural coronary artery systolic stenosis. According to the results of coronary angiography, 156 patients with the myocardial bridge were divided into an atherosclerosis group (the myocardial bridge combined with atherosclerosis at the proximal end of the myocardial bridge of simple wall coronary artery), 91 cases, and a control group (isolated myocardial bridge), 65 cases. The relationship between different degrees of compression and clinical symptoms in patients with the myocardial bridge was observed, and the logistic regression model was used to analyze the risk factors of proximal atherosclerosis in patients with the myocardial bridge., Results: The incidence of atherosclerotic stenosis, angina pectoris, and myocardial infarction in the proximal part of the myocardial bridge in the Noble grades II-III group was higher than that in the Noble grade I group ( P < 0.05). The differences in age, hypertension, and Noble classification between the two groups were statistically significant ( P < 0.05). The differences of total cholesterol (TC) and C-reactive protein (CRP) between the two groups were statistically significant ( P < 0.05). Multivariate analysis showed that age, hypertension, Noble grade, and CRP were all risk factors for proximal atherosclerosis in patients with the myocardial bridge ( P < 0.05)., Conclusion: The more severe the compression of the myocardial bridge, the greater the risk of cardiovascular events for patients and the higher the incidence of atherosclerotic stenosis in the proximal part of the myocardial bridge. In addition, the occurrence of atherosclerosis in the proximal coronary artery of the myocardial bridge may be affected by age, hypertension, Noble grade, and CRP level., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Jiaxi Zhang et al.)

Acute alcoholic liver injury (AALI) is a threat to human health. Dendrobium officinale polysaccharide (DOP) has the potential to protect the liver by enhancing the anti-oxidative system to maintain the relative balance of ROS (active oxygen species) and antioxidants in AALI mice. However, the dynamic improvement effect of DOP on AALI is still not clear and accurate medication guidance is not available, which limits the clinical application of DOP. Because of the advantages of high sensitivity, noninvasiveness, and visualization, near-infrared (NIR) fluorescence imaging has been widely studied in biochemistry and biomedicine. As the glutathione (GSH) level in the liver is closely related to the progression of AALI, herein, an NIR fluorescent probe for GSH, HCG was used to dynamically evaluate the effect of DOP on AALI mice. In this study, DOP was proven to maintain the relative balance of GSH content in the liver to protect it from damage. To the best of our knowledge, it is the first time to assess the effect of DOP on AALI mice through a NIR fluorescence imaging technique. This study may also provide a potential NIR imaging agent for the clinical research to improve the management of liver injury-related diseases., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Our study aimed at validating the effect of WISP1 on osteoarthritis (OA) and the pathway involved in the WISP1-induced protection against OA. The expression of WISP1 was measured by immunohistochemical analyses. We found that WISP1 expression was shown to be upregulated within human OA cartilage compared with controls. WISP1 expression was related to knee OA severity. rhWISP1 inhibited OA chondrocyte senescence and apoptosis in vitro , which was reversed by the αvβ3 antibody and PI3K/Akt inhibitor LY294002. WISP1 overexpression induced by knee injection of LiCI could also prevent the senescence and apoptosis of rat chondrocytes. Safranin-O staining and Mankin score revealed that WISP1 overexpression can protect rat chondrocytes from degeneration. Nearly opposite results were obtained in the treatment of ICG-001 and siRNA-WISP1 in vivo . These data strongly suggest that WISP1 can protect against the senescence and apoptosis of chondrocytes via modulating the αvβ3 receptor and PI3K/Akt signaling pathway within OA. Therefore, the development of specific activators of WISP1 may present the value of an underlying OA treatment.

Nucleus pulposus cell (NPC) is the major cell type maintaining the physiological function of intervertebral discs by producing extracellular matrix (ECM). NPC apoptosis and senescence together contribute to NPC loss, finally leading to intervertebral disc degeneration (IDD). Herein, miR-623 showed to be downregulated within IDD tissue samples according to both bioinformatics and experimental analyses. In LPS-injured NPCs, miR-623 overexpression promoted LPS-suppressed cell proliferation; moreover, miR-623 overexpression inhibited cell apoptosis and senescence, increased ECM secretion, and reduced levels of inflammatory factors. In contrast to miR-623, CXCL12 expression was significantly upregulated in IDD tissues; miR-623 directly bound CXCL12 to inhibit its expression. In LPS-stimulated NPCs, CXCL12 silencing also LPS-induced changes in cell proliferation, cell senescence, ECM secretion, and inflammatory factor levels. More importantly, CXCL12 overexpression aggravated LPS-induced changes and significantly reversed the protective effects of miR-623 overexpression. In conclusion, the miR-623/CXCL12 axis could affect NPC apoptosis and senescence, ECM deposition, and inflammatory factor levels under LPS stimulation in vitro. The p65 signaling might be involved., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Effective stem cell therapy is dependent on the stem cell quality that is determined by their differentiation potential, impairment of which leads to poor engraftment and survival into the target cells. However, limitations in our understanding and the lack of reliable markers that can predict their maturation efficacies have hindered the development of stem cells as an effective therapeutic strategy. Our previous study identified CD10, a pro-adipogenic, depot-specific prospective cell surface marker of human adipose-derived stem cells (ASCs). Here, we aim to determine if CD10 can be used as a prospective marker to predict mature adipocyte quality and play a direct role in adipocyte maturation., Methods: We first generated 14 primary human subject-derived ASCs and stable immortalized CD10 knockdown and overexpression lines for 4 subjects by the lentiviral transduction system. To evaluate the role of CD10 in adipogenesis, the adipogenic potential of the human subject samples were scored against their respective CD10 transcript levels. Assessment of UCP1 expression levels was performed to correlate CD10 levels to the browning potential of mature ASCs. Quantitative polymerase chain reaction (qPCR) and Western blot analysis were performed to determine CD10-dependent regulation of various targets. Seahorse analysis of oxidative metabolism and lipolysis assay were studied. Lastly, as a proof-of-concept study, we used CD10 as a prospective marker for screening nuclear receptor ligands library., Results: We identified intrinsic CD10 levels as a positive determinant of adipocyte maturation as well as browning potential of ASCs. Interestingly, CD10 regulates ASC's adipogenic maturation non-canonically by modulating endogenous lipolysis without affecting the classical peroxisome proliferator-activated receptor gamma (PPARγ)-dependent adipogenic pathways. Furthermore, our CD10-mediated screening analysis identified dexamethasone and retinoic acid as stimulator and inhibitor of adipogenesis, respectively, indicating CD10 as a useful biomarker for pro-adipogenic drug screening., Conclusion: Overall, we establish CD10 as a functionally relevant ASC biomarker, which may be a prerequisite to identify high-quality cell populations for improving metabolic diseases.

Background: Prenatal anxiety has been a significant public health issue globally, leading to adverse health outcomes for mothers and children. The study aimed to evaluate the sociodemographic characteristics, knowledge, attitudes, and practices (KAP), and anxiety level of pregnant women during the coronavirus disease 2019 (COVID-19) epidemic in Wuhan and investigate the influencing factors for prenatal anxiety in this specific context., Methods: Pregnant subjects' KAP towards COVID-19 and their sociodemographics and pregnancy information were collected using questionnaires. The Zung Self-Rating Anxiety Scale (SAS) was used to assess anxiety status. Factors associated with the level of prenatal anxiety were analyzed by Pearson's chi-square test and multivariable logistic regression analyses., Results: The prenatal anxiety prevalence in this population was 20.8%. The mean score of knowledge was 13.2 ± 1.1 on a 0 ~ 14 scale. The attitudes and practices data showed that 580/ 817 (71.0%) were very concerned about the news of COVID-19, 455/817 (55.7%) considered the official media to be the most reliable information source for COVID-19, and 681/817 (83.4%) were anxious about the possibility of being infected by COVID-19. However, only 83/817 (10.2%) worried about contracting COVID-19 infection through the ultrasound transducer during a routing morphology scan. About two-thirds 528/817 (64.6%) delayed or canceled the antenatal visits. Approximately half of them 410/817 (50.2%) used two kinds of personal protection equipments (PPEs) during hospital visits. Logistic regression analysis revealed that the influential factors for prenatal anxiety included previous children in the family, knowledge score, media trust, worry of contracting the COVID-19 infection and worry about getting infected with COVID-19 from the ultrasound probe antenatal care (ANC) schedule., Conclusion: Prenatal anxiety was prevalent among pregnant women in Wuhan during the outbreak of COVID-19. The current findings identified factors associated with the level of prenatal anxiety that could be targeted for psychological care.

PIWI homologs constitute a subclass of the Argonaute family. Traditionally, they have been shown to associate with a specific class of small RNAs, piRNAs, to suppress transposable elements and protect genomic integrity in germ cells. Recent studies imply that PIWI proteins may also exert important biological functions in somatic contexts, including the brain. However, their exact role in neural development remains unknown. Hence we investigated whether PIWI proteins are involved in neuronal differentiation. By using an established cell model for studying neurogenesis, NTera2/D1 (NT2) cells, we found that a particular PIWI homolog, PIWIL4 was increasingly upregulated throughout the course of all-trans retinoic acid (RA)-mediated neuronal differentiation. During this process, PIWIL4 knockdown led to partial recovery of embryonic stem cell markers, while suppressing RA-induced expression of neuronal markers. Consistently, PIWIL4 overexpression further elevated their expression levels. Furthermore, co-immunoprecipitation revealed an RA-induced interaction between PIWIL4 and the H3K27me3 demethylase UTX. Chromatin immunoprecipitation showed that this interaction could be essential for the removal of H3K27me3 from the promoters of RA-inducible genes. By a similar mechanism, PIWIL4 knockdown also suppressed the expression of PTN and NLGN3, two important neuronal factors secreted to regulate glioma activity. We further noted that the conditioned medium collected from PIWIL4-silenced NT2 cells significantly reduced the proliferation of glioma cells. Thus, our data suggest a novel somatic role of PIWIL4 in modulating the expression of neuronal genes that can be further characterized to promote neuronal differentiation and to modulate the activity of glioma cells.

The early prediction of renal outcomes in patients with idiopathic membranous nephropathy (iMN) remains challenging. The present retrospective study evaluated patients with iMN confirmed by renal biopsy. An optimized Cox regression model and a nomogram were constructed for the early prediction of renal outcomes. A total of 141 patients who met the inclusion criteria were evaluated in the present study. In total 18 (12.8%) patients eventually progressed to the endpoint, 6 of whom developed end-stage renal disease, and one patient died during follow-up. The optimized model demonstrated that 24-h proteinuria [hazard ratio (HR) 1.24; 95% CI, 1.10-1.40; P-value <0.001] and chronic tubulointerstitial injury [referred to as grade 0, grade 1 (HR), 5.12; 95% CI, 1.33-19.75; P-value=0.02] or grade 2 (HR, 6.43; 95% CI, 1.35-30.59; P-value=0.02) were independent risk factors for a poor renal outcome. Patients with an estimated three-year renal survival rate (ETR) less than 0.87 had a high risk of a poor renal outcome. In addition, patients with an ETR of 0.87 to 0.98 more quickly developed a decreased estimated glomerular filtration rate after two years of follow-up. In the present study a nomogram for the early prediction of renal outcomes in patients with iMN was developed. This nonogram suggested that patients with an ETR of 0.87-0.98 should receive greater attention during follow-up., (Copyright: © Zhang et al.)

Bariatric surgery results in increased intestinal secretion of hormones GLP-1 and anorexigenic PYY, which is believed to contribute to the clinical efficacy associated with the procedure. This observation raises the question whether combination treatment with gut hormone analogs might recapitulate the efficacy and mitigate the significant risks associated with surgery. Despite PYY demonstrating excellent efficacy and safety profiles with regard to food intake reduction, weight loss, and glucose control in preclinical animal models, PYY-based therapeutic development remains challenging given a low serum stability and half-life for the native peptide. Here, combined peptide stapling and PEG-fatty acid conjugation affords potent PYY analogs with >14 h rat half-lives, which are expected to translate into a human half-life suitable for once-weekly dosing. Excellent efficacy in glucose control, food intake reduction, and weight loss for lead candidate 22 in combination with our previously reported long-acting GLP-1 analog is demonstrated in a diet-induced obesity mouse model.

Background: The association of myocardial bridge (MB) with cardiovascular risk and the possible cardiovascular risk factors remain unclear. This study aimed to explore the clinical characteristics and related factors of coronary stenosis proximal to an MB., Methods: This was a retrospective study of patients with symptoms of coronary atherosclerotic heart disease admitted between 10/2011 and 12/2014 to the Emergency and Cardiology Department of Bayannur Hospital, who underwent selective coronary angiography (SCAG). The patients were assigned to the non-stenosis and stenosis groups according to whether coronary stenosis was proximal to the MB., Results: Among 244 patients with MB and cardiovascular symptoms, 91 (37.3%) had stenosis proximal to the MB. Compared with the non-stenosis group, there were more males (80.2% vs. 55.6%, P < 0.001) and smokers (including those who had quit smoking) (P < 0.001) in the stenosis group. There were no significant differences in blood lipid-related indexes (TG, TC, HDL-C, LDL-C, and VLDL-C) between the two groups. Multivariable analysis suggested that MB location in the middle distal or distal segment of the left anterior descending artery (LAD) increased the odds of coronary stenosis proximal to the MB (OR = 0.439, 95% CI: 1.57-7.532, P = 0.002), which was then considered an independent factor associated with coronary stenosis proximal to the MB., Conclusions: In patients diagnosed with an MB by SCAG, only MB located in the middle distal or distal segment of the LAD is independently associated with coronary stenosis proximal to the MB.

Objective: To elucidate the relationship between the risk factors and hematoma expansion(HE)shapes., Patients and Methods: From February 2013 to November 2018, 60 patients diagnosed as basal ganglia ICH were divided into the filled type hematoma expansion group (FTE group) and the expanded type hematoma expansion group (ETE group). we performed follow-up CT and three-dimensional reconstruction for the patients and compared the hematoma before and after the expansion of size and extent., Results: The regression analysis showed that the irregular sign (odds ratio, 3.64; 95 % CI, 1.46-9.12), black hole sign (odds ratio, 3.85; 95 % CI, 1.40-10.60), blend sign (odds ratio, 2.86; 95 % CI, 1.03-7.95), and early use of dehydration (odds ratio, 4.59; 95 % CI, 1.59-13.19) were possible risk factors for the ETE group, while the high systolic blood pressure (odds ratio, 1.51; 95 % CI, 1.04-2.30), early use of dehydration (odds ratio, 3.27; 95 % CI, 1.10-9.69) and low density low-density band (odds ratio, 4.52; 95 % CI, 1.54-13.28) were possible risk factors for the FTE group., Conclusions: The irregular sign, black hole sign, blend sign and early use of dehydration may be the main risk factors for ETE, whereas early use of dehydration, high systolic blood pressure, and low density low-density band may be the main risk factors for FTE., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Owing to their pleiotropic metabolic benefits, glucagon-like peptide-1 receptor (GLP-1R) agonists have been successfully utilized for treating metabolic diseases, such as type 2 diabetes and obesity. As part of our efforts in developing long-acting peptide therapeutics, we have previously reported a peptide engineering strategy that combines peptide side chain stapling with covalent integration of a serum protein-binding motif in a single step. Herein, we have used this strategy to develop a second generation extendin-4 analog rigidified with a symmetrical staple, which exhibits an excellent in vivo efficacy in an animal model of diabetes and obesity. To simplify the scale-up manufacturing of the lead GLP-1R agonist, a semisynthesis protocol was successfully developed, which involves recombinant expression of the linear peptide followed by attachment of a polyethylene glycol (PEG)-fatty acid staple in a subsequent chemical reaction step.

Cisplatin and other platinum-based compounds are frequently used to treat breast cancer, but their utility is severely compromised by drug resistance. Many genes dictating drug responsiveness are subject to pre-mRNA alternative splicing which is regulated by key kinases such as the serine-arginine protein kinase 1 (SRPK1). However, its contribution to drug resistance remains controversial. In this study, we have identified that Tip60-mediated acetylation of SRPK1 is closely associated with chemotherapy sensitivity. In breast cancer cells, cisplatin induced SRPK1 acetylation but in the corresponding resistant cells, it reduced acetylation yet increased phosphorylation and kinase activity of SRPK1, favouring the splicing of some anti-apoptotic variants. Significantly, the cisplatin-resistant cells could be re-sensitized by enhancing SRPK1 acetylation or inhibiting its kinase activity. Hence, our study reveals a key role of SRPK1 in the development of cisplatin resistance in breast cancer cells and suggests a potential therapeutic avenue for overcoming chemotherapy resistance.

Existing long α-helix mimicking necessitates the retention of most natural amino acid residues to maintain their biological activity. Here, we report the exploration of helical sulfono-γ-AApeptides with entire unnatural backbones for their ability to structurally and functionally mimic glucagon-like peptide 1 (GLP-1). Our findings suggest that efficient construction of novel GLP-1 receptor (GLP-1R) agonists could be achieved with nanomolar potencies. In addition, the resulting sulfono-γ-AApeptides were also proved to display remarkable stability against enzymatic degradation compared to GLP-1, augmenting their biological potential. This alternative strategy of α-helix mimicking, as a proof of concept, could provide a new paradigm to prepare GLP-1R agonists., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Nonylphenol (NP) is considered a major contaminant that must be removed to enable safe and environmentally friendly land application of sewage sludge. Phytoremediation is a technology in which plants are used to remove and/or stabilize organic and inorganic contaminants present in the soil, municipal wastewater, and sewage sludge. In this study, a 391-d large pot experiment was conducted to remove NP from sewage sludge by phytoremediation using Zea mays L. 'Yunshi-5', Lolium perenne L., and co-cropping of the two plants. The fate of NP in the soil under the sewage sludge was assessed at the same time. At the end of the experiment, the NP levels in sludge from the various treatments were as follows: control (38.60%) > L. perenne (31.27%) > Z. mays (16.25%) > co-cropping (15.28%). Degradation followed an availability-adjusted first-order kinetics with a decreasing order of half-lives as follows: control (88.2 d) > L. perenne (87.3 d) > co-cropping (66.2 d) > Z. mays (59.1 d). The results indicated that Z. mays and co-cropping could both degrade NP. The concentrations of NP in tissues of different plants differed significantly. The mean bioconcentration factors for Z. mays and L. perenne were 0.16 and 3.69, respectively. Direct removal of NP from sewage sludge by plant uptake was negligible, as was downward movement of NP in the system. Moreover, NP was not detected in soils in any treatments at harvest., (© 2020 The Authors. Journal of Environmental Quality © 2020 American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America.)

The effects of oxytocin on food intake and body weight reduction have been demonstrated in both animal models and human clinical studies. Despite being efficacious, oxytocin is enzymatically unstable and thus considered to be unsuitable for long-term use in patients with obesity. Herein, a series of oxytocin derivatives were engineered through conjugation with fatty acid moieties that are known to exhibit high binding affinities to serum albumin. One analog ( OT-12 ) in particular was shown to be a potent full agonist at the oxytocin receptor (OTR) in vitro with good selectivity and long half-life (24 h) in mice. Furthermore, OT-12 is peripherally restricted, with very limited brain exposure (1/190 of the plasma level). In a diet-induced obesity mouse model, daily subcutaneous administration of OT-12 exhibited more potent anorexigenic and body weight reducing effects than carbetocin. Thus, our results suggest that the long-acting, peripherally restricted OTR agonist may offer potential therapeutic benefits for obesity.

Objective: To explore the clinical presentation and molecular genetic characteristics of a cohort of congenital hyperinsulinism (CHI) patients from southern China and also to explore the most appropriate therapeutic approaches., Methods: We retrospectively reviewed a cohort of 65 children with CHI. Mutational analysis was performed for KCNJ11 and ABCC8 genes. The GLUD1 gene was sequenced in patients with hyperammonaemia. GCK gene sequencing was performed in those patients with no mutation identified in the ABCC8, KCNJ11 or GLUD1 genes., Results: ABCC8 mutations were identified in 16 (25%) of the cohort, GLUD1 mutations were identified in five children, and no KCNJ11 or GCK mutations were identified. Moreover, some unique features of ABCC8 gene mutations in southern Chinese CHI patients were found in this study. The most common mutation was a deletion/insertion mutation p.Thr1042GlnfsX75 was found in five unrelated patients, which possibly represents a relatively common mutation in southern China. Five novel ABCC8 mutations were detected. The mutations were p.Phe5SerfsX72, p.Gln273ArgfsX85, p.Leu724del, p.Asp1447Gly and IVS 25-1G>T. Five compound heterozygous mutations of ABCC8 gene were identified in this study, and three of these patients were diazoxide-responsive. Forty patients were diazoxide-responsive, 13 patients were diazoxide-unresponsive and 12 patients received dietary treatment only. A pancreatectomy was performed in 10 patients who were unresponsive to medical treatment., Conclusion: To the best of our knowledge, this is the first study of CHI in south China. Mutations in ABCC8 are the most common causes of CHI in this cohort. Diazoxide and dietary treatment were effective in most patients. Multicentre studies are necessary to obtain the long-term follow-up characteristics of such patients at a national level.

Although multilayer stents (MSs) can be used to treat aneurysm effectively, for some aneurysms with branches attached, the hemodynamic mechanisms are still unclear. In this work, we modeled five cases that involve 1-4-layer stents implanted in aneurysms with side branches, and the numerical approach was used. Case 1 corresponds to an aneurysm without a stent, and cases 2-5 represent 1-4-layer stents being employed within aneurysms, respectively. The results showed that the velocity within the sac declined dramatically and the eddies' intensity weakened with increased number of stent layers, time-averaged wall shear stress (TAWSS), and nitric oxide production rate (TAR NO ) dropped linearly with increase in stent porosity, and oscillatory shear index (OSI) and relative residence time (RRT) increased evidently with MS intervention. Moreover, the MSs had a slight effect on the patency of the side branch; its flow rate was still above the normal case than without aneurysm. It can be concluded that MSs are helpful in promoting the growth of thrombus within the aneurysm through an isolated hemodynamic environment and keeping the branch unobstructed, but more clinical evidences are required.

A panel of three lipid-modified, functionalized biphenyl cross-linkers (fBph) were synthesized and subsequently employed in the preparation of the stapled oxyntomodulin (OXM) analogs. In a luciferase-based reporter assay, these stapled OXM analogs showed varying degree of potency in activating GLP-1R and GCGR, presumably due to the disparate effect of the lipid chains on the local environment close to the ligand-receptor binding interface. In particular, the fBph-1 cross-linked peptide with the lipid chain attached to position-3 of the biphenyl cross-linker exhibited the highest dual agonist activity.

Tubular-interstitial nephritis (TIN) is characterized by tubular cell damage and inflammatory lesions of kidneys. Baicalein (BAI) is a flavonoid compound found in the roots of Scutellaria baicalensis Georgi. The present study was undertaken to explore the anti-inflammatory and anti-oxidative effects of BAI on TIN patients and a lipopolysaccharide (LPS)-induced TIN cell model. The expression levels of interleukin-6 (IL-6), IL-10, and tumor necrosis factor α in serum samples of TIN patients and culture supernatants of renal proximal tubular epithelial cells (RPTECs) were evaluated using enzyme-linked immunosorbent assay. Creatinine clearance was calculated using the Cockcroft-Gault equation. Activities of malondialdehyde, superoxide dismutase, and glutathione peroxidase were also determined. Viability and apoptosis of RPTECs were measured using MTT assay and Guava Nexin assay, respectively. qRT-PCR was performed to determine the expressions of Bax, Bcl-2, nuclear factor kappa B (IκBα), and p65. Protein levels of Bax, Bcl-2, IκBα, p65, c-Jun N-terminal kinase, extracellular regulated protein kinases, and p38 were analyzed using western blotting. We found that BAI reduced inflammation and oxidative stress in vivo and in vitro. Moreover, BAI alleviated the LPS-induced RPTECs viability inhibition and apoptosis enhancement, as well as nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) activation. Phorbol ester, an activator of NF-κB, attenuated the effects of BAI on LPS-induced inflammatory cytokine expressions in RPTECs. In conclusion, BAI had anti-inflammatory and anti-oxidative effects on TIN patients and LPS-induced RPTECs by down-regulating NF-κB and MAPK pathways.

IgA nephropathy (IgAN) is an autoimmune disease associated with complement activation. It is unclear whether the ratio of serum C3 and C4 concentrations (C3/C4 ratio) can predict renal outcomes in IgAN patients. A total of 1503 patients diagnosed with IgAN via renal biopsy were recorded in this study. Poor renal outcomes were defined as > 50% decrease in the baseline estimated glomerular filtration rate (eGFR) or development of end-stage renal disease (ESRD) during follow-up. In total, 712 patients meeting the exclusion/inclusion criteria were selected, and the mean follow-up period was 40.6 (12.34) months. Patients with decreased C3/C4 ratios displayed significantly more severe clinical characteristics and renal pathological features and a higher proportion of poor renal outcomes and ESRD. The optimal multivariate Cox regression models identified the C3/C4 ratio (hazard ratio (HR) 0.63, 95% CI 0.5-0.9), serum uric acid (HR 1.58, 95% CI 1.2-2.2), serum creatinine (HR 1.3, 95% CI 1.1-1.6), systolic blood pressure (HR 1.57, 95% CI 1.2-2.0) and T score (relative to T0, T1: HR 1.96, 95% CI 1.1-3.7, T2: HR 3.03, 95% CI 1.6-5.9) as strong predictors of poor renal outcomes. Subgroup analysis showed that patients with low C3/C4 ratios benefited from glucocorticoids or other immunosuppressive agents (hazard ratio 0.30 and 0.18, 95% CI 0.13-0.72 and 0.07-0.46, respectively). Serum C3/C4 ratios may be an independent novel predictor of renal outcomes in IgAN patients. Decreased C3/C4 ratios suggest poor renal outcomes and the potential to benefit from aggressive immunosuppressive therapies.

Objective: The correlation of serum fibroblast growth factor 23 (FGF-23) and Klotho protein levels with bone mineral density (BMD) in maintenance hemodialysis (MHD) patients was analyzed., Methods: Between January 2015 and November 2015, 125 MHD patients in our hospital were enrolled. Dual-energy X-ray absorptiometry was used to examine the BMD in the femoral neck and lumbar spine of MHD patients. The patients were divided into three groups: a normal bone mass group, an osteopenia group, and an osteoporosis group. An ELISA was performed to measure serum FGF-23, Klotho protein, and 1,25(OH) 2 VitD 3 levels. Other parameters, including calcium (Ca), phosphorus (P), and parathyroid hormone, were also measured., Results: Of the 125 MHD patients, 82.40% of patients had femoral neck osteopenia, and 56.00% of patients had lumbar spinal osteopenia. The serum FGF-23 level was highest in the osteoporosis group. However, there was no significant difference in serum FGF-23 levels among the three groups, depending on femoral neck and lumbar spinal BMD (P > 0.05). Spearman's correlation analysis also pointed to a lack of correlation between serum FGF-23 levels and BMD. Among the three groups, there were significant differences in serum Klotho protein levels and femoral neck BMD (P < 0.05). Serum Klotho protein levels in the osteoporosis group were clearly lower than those in the normal bone mass group and osteopenia group (P < 0.05). Similarly, serum Klotho protein levels were significantly lower in those with lumbar spinal osteopenia as compared with those in the normal group. There was a positive correlation between serum Klotho protein levels and BMD and T values for the femoral neck and lumbar spine. The results of a multiple linear regression analysis revealed that the serum Klotho protein level was one of the main factors affecting BMD in MHD patients., Conclusions: The serum level of FGF-23 was not correlated with a change in BMD of MHD patients, whereas the serum Klotho protein level was associated with the degree of BMD. A high Klotho protein level may decrease the severity of chronic kidney disease and mineral bone disorder (CKD-MBD) in MHD patients with low BMD.