Discovery of a Potent Antiosteoporotic Drug Molecular Scaffold Derived from Angelica sinensis and Its Bioinspired Total Synthesis.

Angelica sinensis, commonly known as Dong Quai in Europe and America and as Dang-gui in China, is a medicinal plant widely utilized for the prevention and treatment of osteoporosis. In this study, we report the discovery of a new category of phthalide from Angelica sinensis, namely falcarinphthalides A and B (1 and 2), which contains two fragments, (3R,8S)-falcarindiol (3) and (Z)-ligustilide (4). Falcarinphthalides A and B (1 and 2) represent two unprecedented carbon skeletons of phthalide in natural products, and their antiosteoporotic activities were evaluated. The structures of 1 and 2, including their absolute configurations, were established using extensive analysis of NMR spectra, chemical derivatization, and ECD/VCD calculations. Based on LC-HR-ESI-MS analysis and DFT calculations, a production mechanism for 1 and 2 involving enzyme-catalyzed Diels-Alder/retro-Diels-Alder reactions was proposed. Falcarinphthalide A (1), the most promising lead compound, exhibits potent in vitro antiosteoporotic activity by inhibiting NF-κB and c-Fos signaling-mediated osteoclastogenesis. Moreover, the bioinspired gram-scale total synthesis of 1, guided by intensive DFT study, has paved the way for further biological investigation. The discovery and gram-scale total synthesis of falcarinphthalide A (1) provide a compelling lead compound and a novel molecular scaffold for treating osteoporosis and other metabolic bone diseases.

Characteristics and efficacy of traditional Chinese medicine in the therapeutic strategy of chronic coronary syndrome: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Chronic coronary syndrome (CCS) has always been controversial in its therapeutic strategy. Although invasive treatment and optimal medication therapy (OMT) are the most commonly used treatments, doctors continue to debate the best strategy. However, traditional Chinese medicine (TCM) for CCS is effective clinically. METHODS: To identify potentially eligible observational and experimental studies, we searched Pubmed, the Web of Science, and the China National Knowledge Internet. To be eligible, studies had to report with end-of treatment outcomes, such as major adverse cardiac events (MACE), deaths from myocardial infarctions (MI), all-cause mortality, angina, cardiac mortality, the effectiveness rate of electrocardiographs, and the reduction rate of the Nitroglycerin tablets. Risk differences (RDs) and 95 % confidence intervals (95 % CIs) were calculated based on random-effects models or fixed-effects models. Citation screening, data abstraction, risk assessment, and strength-of-evidence grading were completed by 2 independent reviewers. RESULTS: In Section 1 (13 studies, involving 17,287 patients), showed no significant difference between invasive treatment and medication treatment in MACE (RD = -0.04, 95% CI = -0.08 to 0.00, I2 = 76.4 %), all-cause mortality (RD = -0.01, 95%CI = -0.022 to 0.01, I2 = 73.44 %), MI (RD = 0.00, 95%CI = -0.00 to 0.01, I2 = 0.00 %) and cardiac mortality (RD = 0.00, 95 %CI = -0.01 to 0.01, I2 = 34.9 %). In Section 2 (21 studies, including 1820 patients), compared with WM treatment, TCM + WM treatment increased ECG effectiveness by 18 %, angina effectiveness by 20 %, and stopping or reducing Nitroglycerin tablets by 20 %. In Section 3 (25 studies, including 2859 patients) showed that TCM revealed a better electrocardiogram effective rate (RD = 0.10, 95 %CI = 0.05 to 0.14, I2 = 44.7 %) and angina effective rate (RD = 0.12, 95 %CI = 0.09 to 0.15, I2 = 44.9 %). We identified that TCM treatment properties of "Circulating blood and transforming stasis" and application of warm/heat-properties medicines were frequently used in CCS treatment. CONCLUSIONS: TCM treatment has shown superior beneficial cardioprotective in CCS therapy strategy, among which "Circulating blood and transforming stasis" and the application of warm/heat-properties medicine are its characteristics.

GPCR-mediated regulation of beige adipocyte formation: Implications for obesity and metabolic health.

Obesity and its associated complications pose a significant burden on health. The non-shivering thermogenesis (NST) and metabolic capacity properties of brown adipose tissue (BAT), which are distinct from those of white adipose tissue (WAT), in combating obesity and its related metabolic diseases has been well documented. However, beige adipose tissue, the third and relatively novel type of adipose tissue, which emerges in extensive presence of WAT and shares similar favorable metabolic properties with BAT, has garnered considerable attention in recent years. In this review, we focused on the role of G protein-coupled receptors (GPCRs), the largest receptor family and the most successful class of drug targets in humans, in the induction of beige adipocytes. More importantly, we highlight researchers' clinical treatment attempts to ameliorate obesity and other related metabolic diseases through the formation and activation of beige adipose tissue. In summary, this review provides valuable insights into the formation of beige adipose tissue and the involvement of GPCRs, based on the latest advancements in scientific research.

Fusion of airborne multimodal point clouds for vegetation parameter correction extraction in burned areas.

Most experimental studies use unimodal data for processing, the RGB image point cloud cannot separate the shrub and tree layers according to the visible vegetation index, and the airborne laser point cloud is difficult to distinguish between the ground and grass ranges, to address the above problems, a multi-band information image fusing the LiDAR point cloud and the RGB image point cloud is constructed. In this study, data collected from UAV platforms, including RGB image point clouds and laser point clouds, were used to construct a fine canopy height model (using laser point cloud data) and high-definition digital orthophotos (using image point cloud data), and the orthophotos were fused with a canopy height model (CHM) by selecting the Difference Enhancement Vegetation Index (DEVI) and Normalised Green-Blue Discrepancy Index (NGBDI) after comparing the accuracy of different indices. Morphological reconstruction of CHM + DEVI/NGBDI fusion image, remove unreasonable values; construct training samples, using classification regression tree algorithm, segmentation of the range of the burned areas and adaptive extraction of vegetation as trees, shrubs and grasslands, tree areas as foreground markers using the local maximum algorithm to detect the tree apexes, the non-tree areas are assigned to be the background markers, and the Watershed Transform is performed to obtain the segmentation contour; the original laser point cloud is divided into chunks according to the segmented single-tree contour, and the highest point is traversed to search for the highest point, and corrected for the height of the single-tree elevations one by one. Accuracy analysis of the vegetation information extracted by the method with the measured data showed that the improved method increased the overall recall rate by 4.1%, the overall precision rate by 3.7%, the overall accuracy F1 score by 3.9%, and the tree height accuracy by 8.8%, 1.4%, 1.7%, 6.4%, 1.8%, and 0.3%, respectively, in the six sampling plots. The effectiveness of the improved method is verified, while the higher the degree of vegetation mixing in the region the better the extraction effect of the improved algorithm.

Gubi Zhitong formula alleviates osteoarthritis in vitro and in vivo via regulating BNIP3L-mediated mitophagy.

BACKGROUND: Osteoarthritis (OA) is characterized by degeneration of articular cartilage, leading to joint pain and dysfunction. Gubi Zhitong formula (GBZTF), a traditional Chinese medicine formula, has been used in the clinical treatment of OA for decades, demonstrating definite efficacy. However, its mechanism of action remains unclear, hindering its further application. METHODS: The ingredients of GBZTF were analyzed and performed with liquid chromatography-mass spectrometry (LC-MS). 6 weeks old SD rats were underwent running exercise (25 m/min, 80 min, 0°) to construct OA model with cartilage wear and tear. It was estimated by Micro-CT, Gait Analysis, Histological Stain. RNA-seq technology was performed with OA Rats' cartilage, and primary chondrocytes induced by IL-1ß (mimics OA chondrocytes) were utilized to evaluated and investigated the mechanism of how GBZTF protected OA cartilage from being damaged with some functional experiments. RESULTS: A total of 1006 compounds were identified under positive and negative ion modes by LC-MS. Then, we assessed the function of GBZTF through in vitro and vivo. It was found GBZTF could significantly up-regulate OA rats' limb coordination and weight-bearing capacity, and reduce the surface and sub-chondral bone erosions of OA joints, and protect cartilage from being destroyed by inflammatory factors (iNOS, IL-6, IL-1ß, TNF- α, MMP13, ADAMTS5), and promote OA chondrocytes proliferation and increase the S phage of cell cycle. In terms of mechanism, RNA-seq analysis of cartilage tissues revealed 1,778 and 3,824 differentially expressed genes (DEGs) in model vs control group and GBZTF vs model group, respectively. The mitophagy pathway was most significantly enriched in these DEGs. Further results of subunits of OA chondrocytes confirmed that GBZTF could alleviate OA-associated inflammation and cartilage damage through modulation BCL2 interacting protein 3-like (BNIP3L)-mediated mitophagy. CONCLUSION: The therapeutic effectiveness of GBZTF on OA were first time verified in vivo and vitro through functional experiments and RNA-seq, which provides convincing evidence to support the molecular mechanisms of GBZTF as a promising therapeutic decoction for OA.

Efficacy and safety of ibrexafungerp in the treatment of vulvovaginal candidiasis: A meta-analysis of randomized controlled trials.

Background: This study aims to evaluate the efficacy and safety associated with ibrexafungerp in the treatment of vulvovaginal candidiasis infection patients. Methods: We conducted a comprehensive search of the PubMed, Embase, Cochrane Library, and Clinical Trials databases up to December 25, 2022. The primary outcomes were clinical cure rate and mycological eradication rate, whereas the secondary outcomes were the risk of an adverse events. Results: In total of four studies encompassing 880 patients diagnosed with vulvovaginal candidiasis (VVC) were included in the analysis. The findings demonstrated that ibrexafungerp exhibited superior clinical cure ratio (RR = 1.33 [1.07, 1.66]), mycological eradication rate (RR = 1.72 [1.00, 2.95]), and overall success ratio (RR = 1.64 [0.92, 2.92]) when compared to the fluconazole/placebo in the treatment of VVC. Furthermore, patients treated with ibrexafungerp demonstrated significantly higher clinical cure rates, mycological eradication, and overall success ratio compared to those receiving other treatments for vulvovaginal candidiasis caused by C. albicans. When ibrexafungerp was compared to fluconazole/placebo, the duration of any treatment-related treatment-emergent adverse events (TEAE), nausea, and diarrhea during therapy was significantly longer. Conclusion: In summary, the use of ibrexafungerp was linked to superior clinical cure ratio, and mycological eradication when compared to fluconazole/placebo.

The study of double-network carboxymethyl chitosan/sodium alginate based cryogels for rapid hemostasis in noncompressible hemorrhage.

Developing an injectable hemostatic dressing with shape recovery and high blood absorption ratio for rapid hemostasis in noncompressible hemorrhage maintains a critical clinical challenge. Here, double-network cryogels based on carboxymethyl chitosan, sodium alginate, and methacrylated sodium alginate were prepared by covalent crosslinking and physical crosslinking, and named carboxymethyl chitosan/methacrylated sodium alginate (CM) cryogels. Covalent crosslinking was achieved by methacrylated sodium alginate in the freeze casting process, while physical crosslinking was realized by electrostatic interaction between the amino group of carboxymethyl chitosan and the carboxyl group of sodium alginate. CM cryogels exhibited large water swelling ratios (8167 ± 1062 %), fast blood absorption speed (2974 ± 669 % in 15 s), excellent compressive strength (over 160 kPa for CM100) and shape recovery performance. Compared with gauze and commercial gelatin sponge, better hemostatic capacities were demonstrated for CM cryogel with the minimum blood loss of 40.0 ± 8.9 mg and the lowest hemostasis time of 5.0 ± 2.0 s at hemostasis of rat liver. Made of natural polysaccharides with biocompatibility, hemocompatibility, and cytocompatibility, the CM cryogels exhibit shape recovery and high blood absorption rate, making them promising to be used as an injectable hemostatic dressing for rapid hemostasis in noncompressible hemorrhage.

Clinical Validation of a Targeted Next-Generation Sequencing Panel for Lymphoid Malignancies.

Lymphoid malignancies are a heterogeneous group of hematological disorders characterized by a diverse range of morphologic, immunophenotypic, and clinical features. Next-generation sequencing (NGS) is increasingly being applied to delineate the complex nature of these malignancies and identify high-value biomarkers with diagnostic, prognostic, or therapeutic benefit. However, there are various challenges in using NGS routinely to characterize lymphoid malignancies, including pre-analytic issues, such as sequencing DNA from formalin-fixed, paraffin-embedded tissue, and optimizing the bioinformatic workflow for accurate variant calling and filtering. This study reports the clinical validation of a custom capture-based NGS panel to test for molecular markers in a range of lymphoproliferative diseases and histiocytic neoplasms. The fully validated clinical assay represents an accurate and sensitive tool for detection of single-nucleotide variants and small insertion/deletion events to facilitate the characterization and management of patients with hematologic cancers specifically of lymphoid origin.

A novel prognostic signature of coagulation-related genes leveraged by machine learning algorithms for lung squamous cell carcinoma.

Coagulation-related genes (CRGs) have been demonstrated to be essential for the development of certain tumors; however, little is known about CRGs in lung squamous cell carcinoma (LUSC). In this study, we adopted CRGs to construct a coagulation-related gene prognostic signature (CRGPS) using machine learning algorithms. Using a set of 92 machine learning integrated algorithms, the CRGPS was determined to be the optimal prognostic signature (median C-index = 0.600) for predicting the prognosis of an LUSC patient. The CRGPS was not only superior to traditional clinical parameters (e.g., T stage, age, and gender) and its commutative genes but also outperformed 19 preexisting prognostic signatures for LUSC on predictive accuracy. The CRGPS score was positively correlated with poor prognoses in patients with LUSC (hazard ratio > 1, p < 0.05), indicating its suitability as a prognostic marker for this disease. The CRGPS was observed to be inversely correlated with the degree of infiltration of natural killer cells. For some tumors, patients with lower CRGPS scores are more likely to experience enhanced immunotherapy effects (area under the curve = 0.70), which implies that the CRGPS can potentially predict immunotherapy efficacy. A high CRGPS score is predictive of an LUSC patient being sensitive to several drugs. Collectively, these findings indicate that the CRGPS may be a reliable indicator of the prognoses of patients with LUSC and may be useful for the clinical management of such patients.

Mitigating phospholipid peroxidation of macrophages in stress-induced tumor microenvironment by natural ALOX15/PEBP1 complex inhibitors.

BACKGROUND: The intricate interactions between chronic psychological stress and susceptibility to breast cancer have been recognized, yet the underlying mechanisms remain unexplored. Danzhi Xiaoyao Powder (DZXY), a traditional Chinese medicine (TCM) formula, has found clinical utility in the treatment of breast cancer. Macrophages, as the predominant immune cell population within the tumor microenvironment (TME), play a pivotal role in orchestrating tumor immunosurveillance. Emerging evidence suggests that lipid oxidation accumulation in TME macrophages, plays a critical role in breast cancer development and progression. However, a comprehensive understanding of the pharmacological mechanisms and active components of DZXY related to its clinical application in the treatment of stress-aggravated breast cancer remains elusive. PURPOSE: This study sought to explore the plausible regulatory mechanisms and identify the key active components of DZXY contributing to its therapeutic efficacy in the context of breast cancer. METHODS: Initially, we conducted an investigation into the relationship between the phagocytic capacity of macrophages damaged by psychological stress and phospholipid peroxidation using flow cytometry and LC-MS/MS-based phospholipomics. Subsequently, we evaluated the therapeutic efficacy of DZXY based on the results of the tumor size, tumor weight, the phospholipid peroxidation pathway and phagocytosis of macrophage. Additionally, the target-mediated characterization strategy based on binding of arachidonate 15-lipoxygenase (ALOX15) to phosphatidylethanolamine-binding protein-1 (PEBP1), including molecular docking analysis, microscale thermophoresis (MST) assay, co-immunoprecipitation analysis and activity verification, has been further implemented to reveal the key bio-active components in DZXY. Finally, we evaluated the therapeutic efficacy of isochlorogenic acid C (ICAC) based on the results of tumor size, tumor weight, the phospholipid peroxidation pathway, and macrophage phagocytosis in vivo. RESULTS: The present study demonstrated that phospholipid peroxides, as determined by LC-MS/MS-based phospholipidomics, triggered in macrophages, which in turn compromised their capacity to eliminate tumor cells through phagocytosis. Furthermore, we elucidate the mechanism behind stress-induced PEBP1 to form a complex with ALOX15, thereby mediating membrane phospholipid peroxidation in macrophages. DZXY, demonstrates potent anti-breast cancer therapeutic effects by disrupting the ALOX15/PEBP1 interaction and inhibiting phospholipid peroxidation, ultimately enhancing macrophages' phagocytic capability towards tumor cells. Notably, ICAC emerged as a promising active component in DZXY, which can inhibit the ALOX15/PEBP1 interaction, thereby mitigating phospholipid peroxidation in macrophages. CONCLUSION: Collectively, our findings elucidate stress increases the susceptibility of breast cancer by driving lipid peroxidation of macrophages and suggest the ALOX15/PEBP1 complex as a promising intervention target for DZXY.

TM9SF1 promotes bladder cancer cell growth and infiltration.

BACKGROUND: Bladder cancer (BC) is the most common urological tumor. It has a high recurrence rate, displays tutor heterogeneity, and resists chemotherapy. Furthermore, the long-term survival rate of BC patients has remained unchanged for decades, which seriously affects the quality of patient survival. To improve the survival rate and prognosis of BC patients, it is necessary to explore the molecular mechanisms of BC development and progression and identify targets for treatment and intervention. Transmembrane 9 superfamily member 1 (TM9SF1), also known as MP70 and HMP70, is a member of a family of nine transmembrane superfamily proteins, which was first identified in 1997. TM9SF1 can be expressed in BC, but its biological function and mechanism in BC are not clear. AIM: To investigate the biological function and mechanism of TM9SF1 in BC. METHODS: Cells at 60%-80% confluence were transfected with lentiviral vectors for 48-72 h to achieve stable TM9SF1 overexpression or silencing in three BC cell lines (5637, T24, and UM-UC-3). The effect of TM9SF1 on the biological behavior of BC cells was then investigated through CCK8, wound-healing assay, transwell assay, and flow cytometry. RESULTS: Overexpression of TM9SF1 increased the in vitro proliferation, migration, and invasion of BC cells by promoting the entry of BC cells into the G2/M phase. Silencing of TM9SF1 inhibited in vitro proliferation, migration, and invasion of BC cells and blocked BC cells in the G1 phase. CONCLUSION: TM9SF1 may be an oncogene in BC.

Clinical Significance of Upregulation of EZH1 Expression in Hepatocellular Carcinoma Tissues.

BACKGROUND AND AIMS: The incidence and mortality of hepatocellular carcinoma (HCC) are increasing. It is urgent to develop more effective HCC biomarkers for diagnosis and treatment. This project intends to verify the expression of enhancer of zeste 1 polycomb repressive complex 2 subunit (EZH1) and its mechanism in HCC. METHODS: This study integrates global microarray and high-throughput sequencing datasets, combined with internal immunohistochemistry, to analyze the expression and prognostic value of EZH1 in HCC. Functional enrichment analysis was conducted to investigate transcriptional targets, which were achieved by intersecting HCC over-expressed genes, EZH1 co-expressed genes and putative transcriptional targets. The relationship between EZH1 and anticancer drugs was detected by drug sensitivity analysis. RESULTS: In this study, 84 datasets from 40 platforms (3,926 HCC samples and 3,428 non-cancerous liver tissues) were included to show the high expression of EZH1 in HCC. Immunohistochemistry with 159 HCC samples and 62 non-HCC samples confirmed the high expression level. HCC patients with high EZH1 expression had worse survival prognoses. Gene ontology and Reactome analysis revealed that metabolism-related pathways, including autophagy, are critical for HCC. Interestingly, as one of the EZH1 potential transcriptional targets, autophagy-related 7 (ATG7) appeared in the above pathways. ATG7 was positively correlated with EZH1, upregulated in HCC, and mediated poor prognosis. Upregulation of EZH1 was found to be in contact with HCC anti-tumor drug resistance. CONCLUSIONS: The upregulation of EZH1 expression can promote the occurrence of HCC and lead to poor clinical progression and drug resistance; these effects may be mediated by regulating ATG7.

The 'whole landscape' of research on systemic sclerosis over the past 73 years.

OBJECTIVE: This study aimed to analyse existing research on systemic sclerosis (SSc) conducted over the past 73 years to develop an essential reference for a comprehensive and objective understanding of this field of inquiry. METHODS: Using the Web of Science Core Collection, PubMed, and Scopus databases as data sources for the bibliometric analysis, we searched for published literature related to SSc over the past 73 years. The Bibliometrix package was used to analyse key bibliometric indicators, such as annual publication volume, countries, journals, author contributions, and research hotspots. RESULTS: From 1970 to 2022, the number of SSc articles steadily increased, reaching its peak in 2020-2022, with approximately 1200 papers published in each of these three years. Matucci-Cerinic et al.'s team published the most articles (425). The United States (11,282), Italy (7027), and France (5226) were the most predominant contexts. The most influential scholars in the field were Denton, Leroy, Steen, and Khanna, with H-indices of 86, 84, and 83, respectively. Arthritis and Rheumatism was the most influential journal in this field (H-index 142). High-frequency keywords in the SSc field included fibrosis (738), inflammation (242), vasculopathy (145), fibroblasts (120), and autoantibodies (118) with respect to pathogenesis, and interstitial lung disease (ILD, 708), pulmonary arterial hypertension (PAH, 696), and Raynaud's phenomenon (326) with regards to clinical manifestations. CONCLUSION: In the past three years, SSc research has entered a period of rapid development, mainly driven by research institutions in Europe and the United States. The most influential journal has been Arthritis and Rheumatism, and autoimmune aspects, vasculopathy, fibrogenesis, PAH, and ILD remain the focus of current research and indicate trends in future research.

Unveiling the antioxidant superiority of α-tocopherol: Implications for vitamin E nomenclature and classification.

Since the discovery of tocopherols a century ago, α-tocopherol has been distinguished for its unique biological functions. In this study, we aim to elucidate the unique characteristics of α-tocopherol from a chemical perspective. Utilizing density functional theory (DFT) calculations, we evaluated the thermodynamic and kinetic properties of tocopherols, tocotrienols and their oxidation products. Our findings highlight the superior thermodynamic and kinetic properties of α-tocopherol. Although tocopherol substrates generally exhibit similar reactivities, α-tocopherol is distinguished by a larger gap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) in intermediates, indicating a potential for greater energy release and favoring reaction progression. Moreover, α-tocopherol shows enhanced efficiency in quenching radical intermediates, especially when combined with vitamin C. All these dates provide valuable support for the naming of vitamin E.

Historical context, process, and development trends of pediatric thyroid cancer research: a bibliometric analysis.

Objective: At present, the structure of knowledge in the field of childhood thyroid cancer is not clear enough, and scholars lack a sufficient understanding of the developing trends in this field, which has led to a shortage of forward-looking outputs. The purpose of this research is to help scholars construct a complete knowledge framework and identify current challenges, opportunities, and development trends. Methods: We searched the literature in the Web of Science Core Collection database on August 7, 2023 and extracted key information from the top 100 most cited articles, such as the countries, institutions, authors, themes, and keywords. We used bibliometric tools such as bibliometrix, VOSviewer, and CiteSpace for a visualization analysis and Excel for statistical descriptions. Results: The top 100 most cited articles fluctuated over time, and the research was concentrated in European countries, the United States, and Japan, among which scientific research institutions and scholars from the United States made outstanding contributions. Keyword analysis revealed that research has shifted from simple treatment methods for pediatric thyroid cancer (total thyroidectomy) and inducing factors (the Chernobyl power station accident) to the clinical applications of genetic mutations (such as the BRAF and RET genes) and larger-scale genetic changes (mutation studies of the DICER1 gene). The thematic strategy analysis showed an increasing trend towards the popularity of fusion oncogenes, while the popularity of research on traditional treatments and diagnostics has gradually declined. Conclusion: Extensive research has been conducted on the basic problems of pediatric thyroid cancer, and there has been significant outputs in the follow-up and cohort analysis of conventional diagnostic and treatment methods. However, these methods still have certain limitations. Therefore, scholars should focus on exploring fusion genes, the clinical applications of molecular targets, and novel treatment methods. This study provides a strong reference for scholars in this field.

Association of phthalate exposure with type 2 diabetes and the mediating effect of oxidative stress: A case-control and computational toxicology study.

Phthalic acid esters (PAEs) are widely used as plasticizers and have been suggested to engender adverse effects on glucose metabolism. However, epidemiological data regarding the PAE mixture on type 2 diabetes (T2DM), as well as the mediating role of oxidative stress are scarce. This case-control study enrolled 206 T2DM cases and 206 matched controls in Guangdong Province, southern China. The concentrations of eleven phthalate metabolites (mPAEs) and the oxidative stress biomarker 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine were determined. Additionally, biomarkers of T2DM in paired serum were measured to assess glycemic status and levels of insulin resistance. Significantly positive associations were observed for mono-(2-ethylhexyl) phthalate (MEHP) and Mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) with T2DM (P < 0.001). Restricted cubic spline modeling revealed a non-linear dose-response relationship between MEHHP and T2DM (Pnon-linear = 0.001). The Bayesian kernel machine regression and quantile g-computation analyses demonstrated a significant positive joint effect of PAE exposure on T2DM risk, with MEHHP being the most significant contributor. The mediation analysis revealed marginal evidence that oxidative stress mediated the association between the mPAEs mixture and T2DM, while 8-OHdG respectively mediated 26.88 % and 12.24 % of MEHP and MEHHP on T2DM risk individually (Pmediation < 0.05). Di(2-ethylhexyl) phthalate (DEHP, the parent compound for MEHP and MEHHP) was used to further examine the potential molecular mechanisms by in silico analysis. Oxidative stress may be crucial in the link between DEHP and T2DM, particularly in the reactive oxygen species metabolic process and glucose import/metabolism. Molecular simulation docking experiments further demonstrated the core role of Peroxisome Proliferator Activated Receptor alpha (PPARα) among the DEHP-induced T2DM. These findings suggest that PAE exposure can alter oxidative stress via PPARα, thereby increasing T2DM risk.

Association of glutamate receptor gene polymorphisms with attention-deficit hyperactivity disorder susceptibility: a systematic review and meta-analysis.

Background: There is a growing body of evidence indicating a possible association between genetic variations and attention-deficit hyperactivity disorder (ADHD), although the results have been inconsistent. The objective of this study was to evaluate the correlation between the GRIN2A, GRIN2B and GRM7 gene polymorphisms and ADHD. Methods: A comprehensive meta-analysis and subgroup evaluation was conducted using a fixed-effects model to analyze the association between ADHD and GRIN2B (rs2284411), GRIN2A (rs2229193), and GRM7 (rs3792452) in six genetic models (dominant, recessive, overdominant, homozygous, heterozygous, and allele models). Results: The meta-analysis comprised 8 studies. The overall analysis showed that the GRIN2B rs2284411 T allele and T carries were significantly associated with a decreased risk of ADHD (dominant model:TT + CT vs. CC: OR = 0.783; 95% CI: 0.627-0.980; p = 0.032, allele model:T vs. C: OR = 0.795; 95% CI: 0.656-0.964; p = 0.019), especially in the Korean subgroup (dominant model:TT + CT vs. CC: OR = 0.640; 95% CI: 0.442-0.928; p = 0.019, overdominant model: CT vs. TT + CC: OR = 0.641; 95% CI: 0.438-0.938; p = 0.022, allele model:T vs. C: OR = 0.712; 95% CI: 0.521-0.974; p = 0.034 and heterozygous model: CT vs. CC: OR = 0.630; 95% CI: 0.429-0.925; p = 0.018). However, no meaningful associations were found for rs2229193 and rs3792452. Conclusion: The results of the meta-analysis provide strong evidence that the rs2284411 T allele is significantly associated with reduced susceptibility to ADHD, particularly in the Korean population.

Prognostic impact of SF3B1 mutation and multilineage dysplasia in myelodysplastic syndromes with ring sideroblasts: a Mayo Clinic study of 170 informative cases.

The revised 4th edition of the World Health Organization (WHO4R) classification lists myelodysplastic syndromes with ring sideroblasts (MDS-RS) as a separate entity with single lineage (MDS-RS-SLD) or multilineage (MDS-RS-MLD) dysplasia. The more recent International Consensus Classification (ICC) distinguishes between MDS with SF3B1 mutation (MDS-SF3B1) and MDS-RS without SF3B1 mutation; the latter is instead included under the category of MDS not otherwise specified. The current study includes 170 Mayo Clinic patients with WHO4R-defined MDS-RS, including MDS-RS-SLD (N=83) and MDS-RS-MLD (N=87); a subset of 145 patients were also evaluable for the presence of SF3B1 and other mutations, including 126 with (87%) and 19 (13%) without SF3B1 mutation. Median overall survival for all 170 patients was 6.6 years with 5- and 10-year survival rates of 59% and 25%, respectively. A significant difference in overall survival was apparent between MDS-RS-MLD and MDS-RS-SLD (p<0.01) but not between MDS-RS with and without SF3B1 mutation (p=0.36). Multivariable analysis confirmed the independent prognostic contribution of MLD (HR 1.8, 95% CI 1.1-2.8; p=0.01) and also identified age (p<0.01), transfusion need at diagnosis (p<0.01), and abnormal karyotype (p<0.01), as additional risk factors; the impact from SF3B1 or other mutations was not significant. Leukemia-free survival was independently affected by abnormal karyotype (p<0.01), RUNX1 (0.02) and IDH1 (p=0.01) mutations, but not by MLD or SF3B1 mutation. Exclusion of patients not meeting ICC-criteria for MDSSF3B1 did not change the observations on overall survival. MLD-based, as opposed to SF3B1 mutationbased, disease classification for MDS-RS might be prognostically more relevant.

MMP12 is a Potential Predictive and Prognostic Biomarker of Various Cancers Including Lung Adenocarcinoma.

OBJECTIVE: This study sought to explore the clinical value of matrix metalloproteinases 12 (MMP12) in multiple cancers, including lung adenocarcinoma (LUAD). METHODS: Using >10,000 samples, this retrospective study demonstrated the first pan-cancer analysis of MMP12. The expression of MMP12 between cancer groups and their control groups was analyzed using Wilcoxon rank-sum tests. The clinical significance of MMP12 expression in multiple cancers was assessed using receiver operating characteristic curves, Kaplan-Meier curves, and univariate Cox analysis. A further LUAD-related analysis based on 4565 multi-center and in-house samples was performed to verify the findings regarding MMP12 in pan-cancer analysis partly. RESULTS: MMP12 mRNA is highly expressed in 13 cancers compared to their controls, and the MMP12 protein level is elevated in some of these cancers (e.g., colon adenocarcinoma) (P < .05). MMP12 expression makes it feasible to distinguish 21 cancer tissues from normal tissues (AUC = 0.86). A high MMP12 expression is a prognosis risk factor in eight cancers, such as adrenocortical carcinoma (hazard ratio >1, P < .05). The elevated MMP12 expression is also a prognosis protective factor in breast-invasive carcinoma and colon adenocarcinoma (hazard ratio <1, P < .05). Some pan-cancer findings regarding MMP12 are verified in LUAD-MMP12 expression is upregulated in LUAD at both the mRNA and protein levels (P < .05), has the potential to distinguish LUAD with considerable accuracy (AUC = .91), and plays a risk prognosis factor for patients with the disease (P < .05). CONCLUSIONS: MMP12 is highly expressed in most cancers and may serve as a novel biomarker for the prediction and prognosis of numerous cancers.