Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation.

Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPß, a rate-limiting enzyme in FAO. Although TPß activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPß association results in Nur77 self-sacrifice to protect TPß from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPß interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma.

Identification of pyruvic and maleic acid as potential markers for disease activity and prognosis in chronic urticaria.

BACKGROUND: Population-based studies have highlighted the link between chronic urticaria (CU) and metabolic syndrome, and metabolic alterations have been revealed in CU. However, to our knowledge, a comprehensive metabolomics study on a large cohort of patients with CU has not been reported. OBJECTIVE: We sought to explore the underlying metabolic subtypes and novel metabolite biomarkers for CU diagnosis and therapy. METHODS: Plasma samples from 80 patients with CU and 82 healthy controls were collected for metabolomics quantification and bioinformatics analysis. Another independent cohort consisting of 144 patients with CU was studied to validate the findings. Bone marrow-derived mast cells and mice with IgE-induced passive cutaneous anaphylaxis were used for in vitro and in vivo experiments, respectively. RESULTS: We observed clear metabolome differences between CU patients and healthy controls. Meanwhile, differential metabolites N6-acetyl-l-lysine, l-aspartate, maleic acid, and pyruvic acid were used to construct random forest classifiers and achieved area under receiver operating characteristic curve values greater than 0.85, suggesting their potential as diagnostic biomarkers of CU. More importantly, by exploring the underlying metabolic subtypes of CU, we found that the low abundance of pyruvic acid and maleic acid was significantly related to the activity of CU, poor efficacy of second-generation H1 antihistamines, and short relapse-free time. The results were validated in the independent cohort. Moreover, supplementation with pyruvate or maleate could significantly attenuate IgE-mediated mast cell activation in vitro and in vivo. CONCLUSIONS: Plasma pyruvic acid and maleic acid may be effective biomarkers for predicting disease activity, therapeutic efficacy, and prognosis for patients with CU.

LncRNA MALAT1 facilitates BM-MSCs differentiation into endothelial cells and ameliorates erectile dysfunction via the miR-206/CDC42/PAK1/paxillin signalling axis.

BACKGROUND: Erectile dysfunction (ED) is a common male sexual dysfunction, with an increasing incidence, and the current treatment is often ineffective. METHODS: Vascular endothelial growth factor (VEGFA) was used to treat bone marrow-derived mesenchymal stem cells (BM-MSCs), and their cell migration rates were determined by Transwell assays. The expression of the von Willebrand Factor (vWF)VE-cadherin, and endothelial nitric oxide synthase(eNOS) endothelial markers was determined by qRT‒PCR and Western blot analyses. The MALAT1-induced differentiation of BM-MCs to ECs via the CDC42/PAK1/paxillin pathway was explored by transfecting VEGFA-induced BM-MSC with si-MALAT1 and overexpressing CDC42 and PAK1. The binding capacity between CDC42, PAK1, and paxillin in VEGFA-treated and non-VEGFA-treated BM-MSCs was examined by protein immunoprecipitation. MiR-206 was overexpressed in VEGFA-induced BM-MSC, and the binding sites of MALAT1, miR-206, and CDC42 were identified using a luciferase assay. Sixty male Sprague‒Dawley rats were divided into six groups (n = 10/group). DMED modelling was demonstrated by APO experiments and was assessed by measuring blood glucose levels. Erectile function was assessed by measuring the intracavernosa pressure (ICP) and mean arterial pressure (MAP). Penile erectile tissue was analysed by qRT‒PCR, Western blot analysis, and immunohistochemical staining. RESULTS: MALAT1 under VEGFA treatment conditions regulates the differentiation of BM-MSCs into ECs by modulating the CDC42/PAK1/paxillin axis. In vitro experiments demonstrated that interference with CDC42 and MALAT1 expression inhibited the differentiation of BM-MSCs to ECs. CDC42 binds to PAK1, and PAK1 binds to paxillin. In addition, CDC42 in the VEGFA group had a greater ability to bind to PAK1, whereas PAK1 in the VEGFA group had a greater ability to bind to paxillin. Overexpression of miR-206 in VEGFA-induced BM-MSCs demonstrated that MALAT1 competes with the CDC42 3'-UTR for binding to miR-206, which in turn is involved in the differentiation of BM-MSCs to ECs. Compared to the DMED model group, the ICP/MAP ratio was significantly greater in the three BM-MSCs treatment groups. CONCLUSIONS: MALAT1 facilitates BM-MSC differentiation into ECs by regulating the miR-206/CDC42/PAK1/paxillin axis to improve ED. The present findings revealed the vital role of MALAT1 in the repair of BM-MSCs for erectile function and provided new mechanistic insights into the BM-MSC-mediated repair of DMED.

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

Lower energy intake associated with higher risk of cardiovascular mortality in chronic kidney disease patients on a low-protein diets.

OBJECTIVE: An increasing number of studies shown that inadequate energy intake causes an increase in adverse incidents in chronic kidney disease (CKD) patients on low-protein diets (LPD). The study aimed to investigate the relationship between energy intake and cardiovascular mortality in CKD patients on a LPD. METHODS: This was a cross-sectional study, a total of 4264 CKD patients were enrolled from the NHANES database between 2009 and 2018. Restricted cubic spline plots and Cox regression analysis were used to analyze the association between energy intake and cardiovascular mortality in CKD patients on a LPD. Additionally, a nomogram was constructed to estimate cardiovascular survival in CKD patients on a LPD. RESULTS: Among CKD patients on a LPD in the United States, 90.05% had an energy intake of less than 25 kcal/kg/day, compared to 36.94% in CKD patients on a non-LPD. Energy intake and cardiovascular mortality showed a linear relationship in CKD patients on a LPD, while a 'U-shaped' relationship was observed in CKD patients on a non-LPD. Multifactorial Cox regression models revealed that for Per-standard deviation (Per-SD) decrement in energy intake, the risk of cardiovascular mortality increased by 41% (HR: 1.41, 95% CI: 1.12, 1.77; P = 0.004) in CKD patients on a LPD. The concordance index of the nomogram was 0.79 (95% CI, 0.75, 0.83). CONCLUSION: CKD patients, especially those on a LPD, have significantly inadequate energy intake. Lower energy intake is associated with higher cardiovascular mortality in CKD patients on a LPD.

Association of lymphocyte subsets and cytokines with bone metabolism: a retrospective, cross-sectional study.

BACKGROUND: Previous research has shown that lymphocytes and cytokines can mediate bone metabolism. This study explored the clinical association and predictive ability of lymphocytes and cytokines levels for bone metabolism. METHODS: A total of 162 patients were enrolled in this study. The levels of N-terminal propeptide of type I procollagen (P1NP), ß-collagen degradation product (ß-CTX), total T lymphocytes, immature T lymphocytes, suppressor/cytotoxic T lymphocytes, helper/inducer T lymphocytes, B lymphocytes, natural killer (NK) cells, Interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), IFN-α, interleukin-1 beta (IL-1ß), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and IL12p70 were evaluated. The relationship between these lymphocyte subsets and cytokines with bone metabolic status was examined and their predictive ability for bone metabolic status was assessed. RESULTS: The principal component analysis (PCA) and correlation analysis results varied on differences in lymphocyte subsets and cytokines in various bone metabolism states. Differential analysis revealed significant differences in the absolute counts of B lymphocytes (P < 0.05), level of IL-12p70 (P < 0.05), and IL-8 (P < 0.001) at different P1NP levels. Significant differences were observed in the absolute counts of total T lymphocytes (P < 0.05), B lymphocytes (P < 0.05), the level of IL-6 (P < 0.05), the percentage of B lymphocytes (P < 0.01), and NK cells (P < 0.05) at different ß-CTX levels. Furthermore, the receiver operating characteristic (ROC) curve showed that the absolute count of B lymphocytes and levels of IL-12p70 and IL-8 could be used to evaluate bone formation states, while the absolute counts of T and B lymphocytes, level of IL-6, and percentages of NK cells and B lymphocytes could be used to evaluate bone resorption states. CONCLUSION: The bone metabolism status changed based on the lymphocyte subsets and cytokine levels. Differentially expressed lymphocytes and cytokines could be used to distinguish bone metabolism status.

Clinical efficacy of Zhiyang Xiaozhen granules combined with second-generation antihistamine in the treatment of chronic urticaria. / 止痒消疹颗粒联合第2ä»£æŠ—ç»„èƒºè¯æ²»ç–—æ ¢æ€§è¨éº»ç–¹çš„ä¸´åºŠç–—æ•ˆ.

OBJECTIVES: Chronic urticaria presents a chronic process of recurrent attacks, and its first-line treatment is second-generation antihistamine with limited treatment options. The efficacy of antihistamine varies among individuals and cannot meet the needs of all patients. This study aims to explore the clinical efficacy and safety of Zhiyang Xiaozhen granules combined with antihistamine in the treatment of chronic urticaria patients. METHODS: We retrospectively analyzed the clinical data of patients with chronic urticaria who visited the Xiangya Hospital of Central South University from April 2020 to March 2021. The patients who received conventional second-generation antihistamine treatment were selected as a control group, while the patients who received combined treatment with Zhiyang Xiaozhen granules on the basis of conventional second-generation antihistamine treatment were selected as an observation group. The differences in the Weekly Urticaria Activity Score (UAS7) and Dermatology Life Quality Index (DLQI) between the 2 groups before and 4 weeks after treatment were compared. The Symptom Score Reduce Index (SSRI) was used to evaluate and compare the efficacy of the 2 treatment regimens. RESULTS: After 4 weeks of treatment, the UAS7 levels in both groups were significantly reduced (P=0.001 and P<0.001, respectively). The effective rates of the control group and the observation group were 61.11% and 59.38%, respectively when converting UAS7 to SSRI for efficacy evaluation, and there was no statistically significant difference in efficacy between the 2 groups (P>0.05); however, when converting DLQI to SSRI for efficacy evaluation, the effective rates of the control group and the observation group were 33.33% and 46.88%, respectively, and the difference in efficacy between the 2 groups was statistically significant (P<0.001). There were 3 patients with adverse drug reactions related to drowsiness in both groups. CONCLUSIONS: The combination of Zhiyang Xiaozhen granules and second-generation antihistamine can effectively improve disease activity in patients with chronic urticaria, and the improvement in quality of life is better than that with the second-generation antihistamine alone.

Lipidomic profiling reveals metabolic signatures in psoriatic skin lesions.

Psoriasis is a chronic immune-mediated inflammatory disease. Lipids play an important role in regulating the inflammatory response. However, the alteration of lipids involved in psoriasis particular in skin lesions remain unclear. Here, we performed the lipidomics to investigate lipid profiling in the skin lesions of the imiquimod-induced psoriasis-like dermatitis and psoriasis patients. The findings showed that ceramides phosphate (CerP) and ceramides were enriched in psoriatic lesions compared with controls from both psoriasis patients and psoriasis-like mouse model. Psoriasis patients were classified into two subtypes, the CC1 and CC2, by consensus clustering of these lipid signatures. The CC1 was characterized by the higher levels of CerP, uric acid, and more severe psoriasis, compared with CC2 subtype. Interestingly, ceramide-1-phosphate (C1P), dramatically enriched in CC1 subtype, facilitated imiquimod-induced psoriasis-like inflammatory responses. Mechanistically, C1P induced the expression of inflammatory factors and activated DNA replication and cell cycle signaling pathways in the primary keratinocytes. Inhibiting the production of C1P with ceramide kinase inhibitor effectively alleviated the imiquimod-induced psoriasis-like inflammation. Taken together, we described the landscape of lipids alteration and established lipids classification based on pattern of abundance of lipids in psoriatic skin lesions. Suppression of C1P pathway is a novel potential strategy for psoriasis treatment.

Multi-omics characterization of a scoring system to quantify hypoxia patterns in patients with head and neck squamous cell carcinoma.

BACKGROUND: The 5-year survival rate of patients with head and neck squamous cell carcinoma (HNSCC) remains < 50%. Hypoxia patterns are a hallmark of HNSCC that are associated with its occurrence and progression. However, the precise role of hypoxia during HNSCC, such as the relationship between hypoxia, tumor immune landscape and cell communication orchestration remains largely unknown. The current study integrated data from bulk and single-cell RNA sequencing analyses to define the relationship between hypoxia and HNSCC. METHODS: A scoring system named the hypoxia score (HS) was constructed based on hypoxia-related genes (HRGs) expression. The predictive value of HS response for patient outcomes and different treatments was evaluated. Single-cell datasets and cell communication were utilized to rule out cell populations which hypoxia targeted on. RESULTS: The survival outcomes, immune/Estimate scores, responses to targeted inhibitors, and chemotherapeutic, and immunotherapy responses were distinct between a high HS group and a low HS group (all P < 0.05). Single-cell datasets showed different distributions of HS in immune cell populations (P < 0.05). Furthermore, HLA-DPA1/CD4 axis was identified as a unique interaction between CD4 + T Conv and pDC cells. CONCLUSIONS: Altogether, the quantification for hypoxia patterns is a potential biomarker for prognosis, individualized chemotherapeutic and immunotherapy strategies. The portrait of cell communication characteristics over the HNSCC ecosystem enhances the understanding of hypoxia patterns in HNSCC.

Adenosine 5'monophosphate-activated protein kinase activation reduces the risks of psoriasis and its comorbidities: a mendelian randomisation study in the UK Biobank.

OBJECTIVE: Whether metformin and its adenosine 5'monophosphate-activated protein kinase (AMPK) activation protect from psoriasis risk is unconcluded. We investigated the effect of AMPK, a pharmacological target of metformin, on the risk of psoriasis and its comorbidities and mortality among participants in the UK Biobank(UKB). METHODS: To avoid immortal-time-biases in pharmacoepidemiologic studies, Mendelian randomisation was used to infer the AMPK pathway-dependent effects. The cut-off age for distinguishing early-onset/late-onset psoriasis (EOP/LOP) was set at 60 years, based on the incident psoriasis peak in UKB. A genetic instrument comprising 44 single-nucleotide polymorphisms associated with HbA1c, serving as a proxy for AMPK genetic risk score (negatively associated with AMPK activation), was employed as previously reported in the literature. Log-binomial models were used to estimate the effect size of AMPK regarding relative risk (RR) and 95% confidence interval (CI). RESULTS: A total of 407 159 participants were analyzed, including 9,126 EOP and 3,324 LOP. The AMPK-genetic-risk-score was associated with a 12.4% increase in the risk of LOP in men (RR = 1.124, 95% CI: 1.022-1.236). This association was not significant for EOP or women. AMPK genetic risk score exhibited an elevated risk of ischemic heart disease (RR = 1.217, 95% CI 1.062-1.395) in male psoriasis patients. CONCLUSIONS: AMPK activation may protect against LOPs and associated ischemic heart disease in men. A sex-specific, comorbidity-targeted intervention for psoriasis is needed.

Application of magnetic resonance image compilation (MAGiC) in the diagnosis of middle-aged and elderly women with osteoporosis.

OBJECTIVE: To investigate the feasibility of diagnosing osteoporosis (OP) in women through magnetic resonance image compilation (MAGiC). METHODS: A total of 110 patients who underwent lumbar magnetic resonance imaging and dual X-ray absorptiometry examinations were collected and divided into two groups according bone mineral density: osteoporotic group (OP) and non-osteoporotic group (non-OP). The variation trends of T1 (longitudinal relaxation time), T2 (transverse relaxation time) and BMD (bone mineral density) with the increase of age, and the correlation of T1 and T2 with BMD were examined by establishing a clinical mathematical model. RESULTS: With the increase of age, BMD and T1 value decreased gradually, while T2 value increased. T1 and T2 had statistical significance in diagnosing OP (P < 0.001), and there is moderate positive correlation between T1 and BMD values (R = 0.636, P < 0.001), while moderate negative correlation between T2 and BMD values (R=-0.694, P < 0.001). Receiver characteristic curve test showed that T1 and T2 had high accuracy in diagnosing OP (T1 AUC = 0.982, T2 AUC = 0.978), and the critical values of T1 and T2 for evaluating osteoporosis were 0.625s and 0.095s, respectively. Besides, the combined utilization of T1 and T2 had higher diagnostic efficiency (AUC = 0.985). Combined T1 and T2 had higher diagnostic efficiency (AUC = 0.985). Function fitting results of OP group: BMD=-0.0037* age - 0.0015*T1 + 0.0037*T2 + 0.86, sum of squared error (SSE) = 0.0392, and non-OP group: BMD = 0.0024* age - 0.0071*T1 + 0.0007*T2 + 1.41, SSE = 0.1007. CONCLUSION: T1 and T2 value of MAGiC have high efficiency in diagnosing OP by establishing a function fitting formula of BMD with T1, T2 and age.

Lysophosphatidylcholine facilitates the pathogenesis of psoriasis through activating keratinocytes and T cells differentiation via glycolysis.

BACKGROUND: Although abnormal metabolism plays a critical role in the pathogenesis of psoriasis, the details are unclear. OBJECTIVES: Here, we identified to explore the role and mechanism of lysophosphatidylcholine (LPC) on the pathogenesis of psoriasis. METHODS: The level of LPC in plasma and skin lesions and the expression of G2A on skin lesions of psoriasis patients were detected by enzyme-linked immunosorbent assay, liquid chromatography-tandem mass spectrometry, or immunohistochemistry, respectively. The glycolysis in the skin lesions of imiquimod (IMQ)-induced psoriasis-like mouse model was detected by extracellular acidification rate. LPC was subcutaneously injected into IMQ-treated mouse ears, and the phenotype as well as the glycolysis were evaluated. Exploring the effects and mechanism of LPC on keratinocytes and CD4+ T cells by culturing primary keratinocytes and CD4+ T in vitro. RESULTS: We found that LPC was significantly increased both in the plasma and skin lesions of psoriatic patients, while G2A, exerting an essential role in LPC-inducing biological functions, was increased in psoriatic lesions. The abundance of LPC was positively correlated with glycolytic activity in the psoriasis-like mouse model. LPC treatment facilitated psoriasis-like inflammation and glycolytic activity in skin lesions. Mechanistically, the LPC/G2A axis significantly triggered glycolytic activity and produced inflammatory factors in keratinocytes, and blockade of glycolysis abrogated LPC-induced expression of inflammatory mediators in keratinocytes. LPC activated STAT1, resulting in recognition and binding to the promoters of GCK and PKLR, which are glycolytic rate-limiting enzymes. Furthermore, the LPC/G2A axis directly benefited Th1 differentiation, which was dependent on LPC-induced glycolytic activity. Notably, LPC indirectly facilitated Th17 differentiation by inducing the secretion of IL-1ß in keratinocytes-T cells coculture system. CONCLUSIONS: Taken together, our findings revealed the role of the LPC/G2A axis in the pathogenesis of psoriasis; targeting LPC/G2A is a potential strategy for psoriasis therapy.

The relationship between bile acids levels and the prognosis of patients with diabetes on maintenance hemodialysis: a retrospective study.

OBJECTIVE: There is a paucity of research on the association between bile acids (BAs) levels and all-cause death in patients with diabetes mellitus (DM) on maintenance hemodialysis (MHD). This study aimed to investigate the clinical characteristics of patients with DM on MHD according to different BAs levels and their impact on prognosis. METHODS: A retrospective cohort of 1,081 patients on hemodialysis at Xindu People's Hospital and the First Affiliated Hospital of Chengdu Medical College were enrolled. Demographic and clinical characteristics were collected. The relationship between BAs and all-cause death risk was fitted using restricted cubic splines (RCS), and the BAs cutoff value was calculated. Patients were divided into low and high BAs groups based on the cutoff value. The primary endpoint was all-cause death and the secondary outcomes were deaths from cardiovascular events. RESULTS: Finally, 387 patients with DM on MHD were included. The median BAs level of all patients was 4.0 µmol/L. The RCS-based BAs cutoff value was 3.5 µmol/L. The BAs levels correlated negatively with total cholesterol, low-density lipoprotein, and blood calcium levels. During the follow-up, 21.7% of the patients died. The multivariate Cox regression analysis demonstrated that patients with DM on MHD with higher BAs were associated independently with a decreased risk of all-cause death (HR =0.55; 95% CI, 0.35-0.81, p = 0.01) compared to those with lower BAs levels. CONCLUSIONS: Higher BAs levels were associated with lower lipid levels in patients with DM on MHD. BAs is an independent risk factor for all-cause death in patients with DM on MHD.

Research Progress of Vertical Channel Thin Film Transistor Device.

Thin film transistors (TFTs) as the core devices for displays, are widely used in various fields including ultra-high-resolution displays, flexible displays, wearable electronic skins and memory devices, especially in terms of sensors. TFTs have now started to move towards miniaturization. Similarly to MOSFETs problem, traditional planar structure TFTs have difficulty in reducing the channel's length sub-1µm under the existing photolithography technology. Vertical channel thin film transistors (V-TFTs) are proposed. It is an effective solution to overcome the miniaturization limit of traditional planar TFTs. So, we summarize the different aspects of VTFTs. Firstly, this paper introduces the structure types, key parameters, and the impact of different preparation methods in devices of V-TFTs. Secondly, an overview of the research progress of V-TFTs' active layer materials in recent years, the characteristics of V-TFTs and their application in examples has proved the enormous application potential of V-TFT in sensing. Finally, in addition to the advantages of V-TFTs, the current technical challenge and their potential solutions are put forward, and the future development trend of this new structure of V-TFTs is proposed.

Tracking contaminants in groundwater flowing across a river bottom within a complex karst system: Clues from hydrochemistry, stable isotopes, and tracer tests.

Tracking contaminants in karst aquifers is challenging because of the high heterogeneity encountered in carbonate rocks. Multi-tracer tests, combined with chemical and isotopic analyses, were conducted to solve a groundwater contamination incident within a complex karst aquifer in Southwest China. Results showed that: (1) the wastewater from a paper mill, public sewers, and septic tanks were the three main potential contaminant sources identified by chemical and isotopic methods; (2) a direct effect of the paper mill wastewater with high Na+ (up to 2230.5 mg/L) and chemical oxygen demand (COD) concentrations on spring water quality was confirmed by multi-tracer tests, which changed the water type from Ca-HCO3 in the 1970s to Ca-Na-HCO3 in the present study and resulted in a depleted carbon isotope value (-16.5‰); and (3) the studied aquifer is a highly complex karst system, due to two conduits crossed each other without mixing, contaminants traveled a long distance (up to 14 km) within the lower conduit, paper mill-contaminated groundwater flowed across a river bottom and discharged to the opposite bank, and an active subsurface divide occurred. After several months of operation, the groundwater restoration measure based on karst hydrogeologic conditions proved that cutting off contaminant sources for karst aquifer self-restore was effective in practice, which contributed to the decline in NH4+ (from 7.81 mg/L to 0.04 mg/L), Na+ (from 50.12 mg/L to 4.78 mg/L), and COD (from 16.42 mg/L to 0.9 mg/L) concentrations coupled with an increase in δ13C-DIC value (from -16.5‰ to -8.4‰) in the earlier contaminated karst spring. This study's integrated method is expected to screen and confirm contaminant sources within complex karst systems rapidly and effectively, thereby contributing to karst groundwater environmental management.

[circ_0092315 Promotes Proliferation and Invasion of Papillary Thyroid Carcinoma Cells via Regulating microRNA-1256/High Mobility Group A2 axis].

Objective To investigate the role and mechanism of circ_0092315 in the proliferation and invasion of papillary thyroid carcinoma cells. Methods The expression of circ_0092315 in papillary thyroid carcinoma cells was examined by real-time fluorescence quantitative PCR.The proliferation and invasion of TPC-1 cells was assessed by CCK-8 and Transwell assays.The protein level of high mobility group A2 (HMGA2) was determined by Western blotting.The regulatory relationship of circ_0092315,microRNA-1256 (miR-1256),and HMGA2 was explored by bioinformatics tools,dual-luciferase reporter assay,real-time fluorescence quantitative PCR,and Western blotting. ++++Results circ_0092315 was overexpressed in papillary thyroid carcinoma cells (all P<0.001).circ_0092315 promoted the proliferation and invasion of TPC-1 cells (all P<0.001).The transfection of si-circ_0092315 up-regulated the expression of miR-1256 (P<0.001),and miR-1256 inhibitor up-regulated the protein level of HMGA2 (P<0.001). ++++Conclusion circ_0092315 is overexpressed in TPC-1 cells and it promotes the proliferation and invasion of TPC-1 cells by regulating the miR-1256/HMGA2 axis.

Novel chloroquine derivative suppresses melanoma cell growth by DNA damage through increasing ROS levels.

Melanoma is a fatal cancer with a significant feature of resistance to traditional chemotherapeutic drugs and radiotherapy. A mutation in the kinase BRAF is observed in more than 66% of metastatic melanoma cases. Therefore, there is an urgent need to develop new BRAF-mutant melanoma inhibitors. High-dose chloroquine has been reported to have antitumour effects, but it often induces dose-limiting toxicity. In this study, a series of chloroquine derivatives were synthesized, and lj-2-66 had the best activity and was selected for further investigation. Furthermore, the anti-BRAF-mutant melanoma effect and mechanism of this compound were explored. CCK-8 and colony formation assays indicated that lj-2-66 significantly inhibited the proliferation of BRAF-mutant melanoma cells. Flow cytometry revealed that lj-2-66 induced G2/M arrest in melanoma cells and promoted apoptosis. Furthermore, lj-2-66 increased the level of ROS in melanoma cells and induced DNA damage. Interestingly, lj-2-66 also played a similar role in BRAF inhibitor-resistant melanoma cells. In summary, we found a novel chloroquine derivative, lj-2-66, that increased the level of ROS in melanoma cells and induced DNA damage, thus leading to G2/M arrest and apoptosis. These findings indicated that lj-2-66 may become a potential therapeutic drug for melanoma harbouring BRAF mutations.

Advancements in the characterization of tissue resident memory T cells in skin disease.

The newly discovered subset of memory T cells, tissue resident memory T (TRM) cells, reside in peripheral tissues for a long time, contributing to a rapid immune response and constituting the first line of defense when pathogens invade cells. Tissue resident memory T cells have unique transcriptome characteristics, and their presence in peripheral tissues is regulated by many factors. TRM cells residing in different tissues often express different surface markers. In addition to CD8+ and CD4+ T cells, which are the best-characterized T cells, Treg cells and various innate T cells can reside in nonlymphoid tissues. Many recent studies have shown that tissue resident memory T cells play indispensable roles in tumor immunity and allergic diseases. This paper reviews the differentiation, regulation, variety and function of TRM cells and the roles they play in skin diseases, including cutaneous melanoma and psoriasis.

Pharmacogenomics for the efficacy and side effects of antihistamines.

Antihistamines, especially H1 antihistamines, are widely used in the treatment of allergic diseases such as urticaria and allergic rhinitis, mainly for reversing elevated histamine and anti-allergic effects. Antihistamines are generally safe, but some patients experience adverse reactions, such as cardiotoxicity, central inhibition and anticholinergic effects. There are also individual differences in antihistamine efficacy in clinical practice. The concept of individualized medicine has been deeply rooted in people's minds since it was put forward. Pharmacogenomics is the study of the role of inheritance in individual variations in drug response. In recent decades, pharmacogenomics has been developing rapidly, which provides new ideas for individualized medicine. Polymorphisms in the genes encoding metabolic enzymes, transporters and target receptors have been shown to affect the efficacy of antihistamines. In addition, recent evidence suggests that gene polymorphisms influence urticaria susceptibility and antihistamine therapy. Here, we summarize current reports in this area, aiming to contribute to future research in antihistamines and clinical guidance for antihistamines use in individualized medicine.

Lachnospira is a signature of antihistamine efficacy in chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is a mast cell-driven disease with many advances in its aetiology and pathogenesis over the past years. The main treatment of CSU is oral second-generation antihistamines. However, only an average of 50% of CSU patients responded adequately to conventional or quadruple doses of non-sedative antihistamines. Meanwhile, gut microbiota can affect the efficacy of drugs. The purpose of this study was to investigate the relationship between gut microbiota and the efficacy of antihistamines in patients with CSU. The patients with CSU were divided into responders and non-responders according to the efficacy of antihistamine monotherapy. The gut microbiota of faecal samples from 15 responders and 15 non-responders was detected by 16S rDNA sequencing, and the differential bacterial species between the two groups were verified by quantitative polymerase chain reaction (qPCR). Additional faecal samples from 30 responders and 30 non-responders were used as an extended cohort to further verify the above differential bacterial species by qPCR. Lachnospiraceae and its subordinate taxa were found to be the main differences in gut microbiota between responders and non-responders. The abundance of Lachnospira in responders was higher than that in non-responders. Lachnospira exhibits moderate diagnostic value in evaluating the efficacy of antihistamine. Lachnospira is a signature for predicting the efficacy of antihistamine in patients with CSU.