International treaties have mostly failed to produce their intended effects.

There are over 250,000 international treaties that aim to foster global cooperation. But are treaties actually helpful for addressing global challenges? This systematic field-wide evidence synthesis of 224 primary studies and meta-analysis of the higher-quality 82 studies finds treaties have mostly failed to produce their intended effects. The only exceptions are treaties governing international trade and finance, which consistently produced intended effects. We also found evidence that impactful treaties achieve their effects through socialization and normative processes rather than longer-term legal processes and that enforcement mechanisms are the only modifiable treaty design choice with the potential to improve the effectiveness of treaties governing environmental, human rights, humanitarian, maritime, and security policy domains. This evidence synthesis raises doubts about the value of international treaties that neither regulate trade or finance nor contain enforcement mechanisms.

Broadband Achromatic Imaging of a Metalens with Optoelectronic Computing Fusion.

The remarkable ultrathin ability of metalenses gives them potential as a next-generation imaging candidate. However, the inherent chromatic aberration of metalenses restricts their widespread application. We present an achromatic metalens with optoelectronic computing fusion (OCF) to mitigate the impact of chromatic aberration and simultaneously avoid the significant challenges of nanodesign, nanofabrication, and mass production of metalenses, a method different from previous methods. Leveraging the nonlinear fitting, we demonstrate that OCF can effectively learn the chromatic aberration mapping of metalens and thus restore the chromatic aberration. In terms of the peak signal-to-noise ratio index, there is a maximum improvement of 12 dB, and ∼8 ms is needed to correct the chromatic aberration. Furthermore, the edge extraction of images and super-resolution reconstruction that effectively enhances resolution by a factor of 4 are also demonstrated with OCF. These results offer the possibility of applications of metalenses in mobile cameras, virtual reality, etc.

Quantified Metabolomics and Lipidomics Profiles Reveal Serum Metabolic Alterations and Distinguished Metabolites of Seven Chronic Metabolic Diseases.

The co-occurrence of multiple chronic metabolic diseases is highly prevalent, posing a huge health threat. Clarifying the metabolic associations between them, as well as identifying metabolites which allow discrimination between diseases, will provide new biological insights into their co-occurrence. Herein, we utilized targeted serum metabolomics and lipidomics covering over 700 metabolites to characterize metabolic alterations and associations related to seven chronic metabolic diseases (obesity, hypertension, hyperuricemia, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, fatty liver) from 1626 participants. We identified 454 metabolites were shared among at least two chronic metabolic diseases, accounting for 73.3% of all 619 significant metabolite-disease associations. We found amino acids, lactic acid, 2-hydroxybutyric acid, triacylglycerols (TGs), and diacylglycerols (DGs) showed connectivity across multiple chronic metabolic diseases. Many carnitines were specifically associated with hyperuricemia. The hypercholesterolemia group showed obvious lipid metabolism disorder. Using logistic regression models, we further identified distinguished metabolites of seven chronic metabolic diseases, which exhibited satisfactory area under curve (AUC) values ranging from 0.848 to 1 in discovery and validation sets. Overall, quantitative metabolome and lipidome data sets revealed widespread and interconnected metabolic disorders among seven chronic metabolic diseases. The distinguished metabolites are useful for diagnosing chronic metabolic diseases and provide a reference value for further clinical intervention and management based on metabolomics strategy.

Lycopene ε-cyclase mediated transition of α-carotene and ß-carotene metabolic flow in carrot fleshy root.

The accumulation of carotenoids, such as xanthophylls, lycopene, and carotenes, is responsible for the color of carrot (Daucus carota subsp. sativus) fleshy roots. The potential role of DcLCYE, encoding a lycopene ε-cyclase associated with carrot root color, was investigated using cultivars with orange and red roots. The expression of DcLCYE in red carrot varieties was significantly lower than that in orange carrots at the mature stage. Furthermore, red carrots accumulated larger amounts of lycopene and lower levels of α-carotene. Sequence comparison and prokaryotic expression analysis revealed that amino acid differences in red carrots did not affect the cyclization function of DcLCYE. Analysis of the catalytic activity of DcLCYE revealed that it mainly formed ε-carotene, while a side activity on α-carotene and γ-carotene was also observed. Comparative analysis of the promoter region sequences indicated that differences in the promoter region may affect the transcription of DcLCYE. DcLCYE was overexpressed in the red carrot 'Benhongjinshi' under the control of the CaMV35S promoter. Lycopene in transgenic carrot roots was cyclized, resulting in the accumulation of higher levels of α-carotene and xanthophylls, while the ß-carotene content was significantly decreased. The expression levels of other genes in the carotenoid pathway were simultaneously upregulated. Knockout of DcLCYE in the orange carrot 'Kurodagosun' by CRISPR/Cas9 technology resulted in a decrease in the α-carotene and xanthophyll contents. The relative expression levels of DcPSY1, DcPSY2, and DcCHXE were sharply increased in DcLCYE knockout mutants. The results of this study provide insights into the function of DcLCYE in carrots, which could serve as a basis for creating colorful carrot germplasms.

Fluorescence Biosensing Based on Bifurcated DNA Scaffold-Aggregated Ag Nanocluster via Responsive Conformation Switch of Quasi-Molecular Beacon.

To address the limitations of typical hairpin-structural molecular beacons, exploring the ability of a quasi-molecular beacon (qMB) to create label-free fluorescence biosensors is intriguing and remains a challenge. Herein, we propose the first example of modular qMB with the feature of a stimulation-responsive conformation switch to develop an aggregated Ag nanocluster (aAgNC) in a bifurcated DNA scaffold for fluorescently sensing a specific initiator (I*). This qMB was well designed to program four functional modules: I*-recognizable element adopting metastable stem-loop bihairpin structure and two DNA splits (exposed C3GT4 and locked C4AC4T) of aAgNC template that is separated by a tunable hairpin spacer for the customized combination of selective recognition and signaling readout. When presenting I* in an assay route, the specific hybridization induces the directional disassembly of the bihairpin unit, on which the qMB is configurationally switched to liberate the locked split. Thus, the bifurcated parent template pair of C3GT4/C4AC4T is proximal, affording in situ nucleation and clustering of emissive aAgNC. By collecting the fluorescence signal, the quantitative detection of I* is achieved. Benefiting from the ingenious programming of qMB, the recognizing and signaling integration actuates the construction of a facile and convenient fluorescent biosensor featuring rapid reaction kinetics, a wide linear range, high sensitivity, and specificity. This would provide a new paradigm to exploit versatile qMB-based biosensing platforms via stimulation-responsive conformation switches for developing various DNA-scaffolded Ag clusters.

Stimulus-Responsive Four-Stranded DNA Nanoring Assembly to Host Multiple Nanosilver Clusters for Cooperatively Enhanced Fluorescence Biosensing.

Exploring the ability of four-stranded DNA nanorings (fsDNRs) to host multiple nanosilver clusters (NAgCs) for cooperatively amplifiable fluorescence biosensing to a specific initiator (tI*) is fascinating. By designing three DNA single strands and three analogous stem-loop hairpins, we developed a functional fsDNR through sequential cross-opening and overlapped hybridization. Note that a substrate strand (SS) was programmed with six modules: two severed splits (sT and sT') of NAgCs template, two sequestered segments by a middle unpaired spacer, and a partition for tI*-recognizable displacement, while sT and sT' were also tethered in two ends of three hairpins. At first, a triple dsDNA complex with stimulus-responsiveness was formed to guide the specific binding to tI*, while the exposed toehold of the SS activated the forward cascade hybridization of three hairpins, until the ring closure in the tailored self-assembly pathway for forming the fsDNR. The resulting four duplexes forced each pair of sT/sT' to be merged as the parent template in four nicks, guiding the preferential synthesis of four clusters in the shared fsDNR, thereby cooperatively amplifying the green fluorescence signal for sensitive assay of tI*. Meanwhile, the topological conformation of fsDNR can be stabilized by the as-formed cluster adducts to rivet the pair of two splits in the nicks. Benefitting from the self-enhanced effect of multiple emitters, this label-free fluorescent sensing strategy features simplicity, rapidity, and high on-off contrast, without involving complicated nucleic acid amplifiers.

Overcoming the impacts of two-step batch effect correction on gene expression estimation and inference.

Nonignorable technical variation is commonly observed across data from multiple experimental runs, platforms, or studies. These so-called batch effects can lead to difficulty in merging data from multiple sources, as they can severely bias the outcome of the analysis. Many groups have developed approaches for removing batch effects from data, usually by accommodating batch variables into the analysis (one-step correction) or by preprocessing the data prior to the formal or final analysis (two-step correction). One-step correction is often desirable due it its simplicity, but its flexibility is limited and it can be difficult to include batch variables uniformly when an analysis has multiple stages. Two-step correction allows for richer models of batch mean and variance. However, prior investigation has indicated that two-step correction can lead to incorrect statistical inference in downstream analysis. Generally speaking, two-step approaches introduce a correlation structure in the corrected data, which, if ignored, may lead to either exaggerated or diminished significance in downstream applications such as differential expression analysis. Here, we provide more intuitive and more formal evaluations of the impacts of two-step batch correction compared to existing literature. We demonstrate that the undesired impacts of two-step correction (exaggerated or diminished significance) depend on both the nature of the study design and the batch effects. We also provide strategies for overcoming these negative impacts in downstream analyses using the estimated correlation matrix of the corrected data. We compare the results of our proposed workflow with the results from other published one-step and two-step methods and show that our methods lead to more consistent false discovery controls and power of detection across a variety of batch effect scenarios. Software for our method is available through GitHub (https://github.com/jtleek/sva-devel) and will be available in future versions of the $\texttt{sva}$ R package in the Bioconductor project (https://bioconductor.org/packages/release/bioc/html/sva.html).

NIR-II Surface-Enhanced Raman Scattering Nanoprobes in Biomedicine: Current Impact and Future Directions.

The field of second near-infrared (NIR-II) surface-enhanced Raman scattering (SERS) nanoprobes has made commendable progress in biomedicine. This article reviews recent advances and future development of NIR-II SERS nanoprobes. It introduces the fundamental principles of SERS nanoprobes and highlights key advances in the NIR-II window, including reduced tissue attenuation, deep penetration, maximized allowable exposure, and improved photostability. The discussion of future directions includes the refinement of nanoprobe substrates, emphasizing the tailoring of optical properties of metallic SERS-active nanoprobes, and exploring non-metallic alternatives. The intricacies of designing Raman reporters for the NIR-II resonance and the potential of these reporters to advance the field are also discussed. The integration of artificial intelligence (AI) into nanoprobe design represents a cutting-edge approach to overcome current challenges. This article also examines the emergence of deep Raman techniques for through-tissue SERS detection, toward NIR-II SERS tomography. It acknowledges instrumental advancements like improved charge-coupled device sensitivity and accelerated imaging speeds. The article concludes by addressing the critical aspects of biosafety, ease of functionalization, compatibility, and the path to clinical translation. With a comprehensive overview of current achievements and future prospects, this review aims to illuminate the path for NIR-II SERS nanoprobes to innovate diagnostic and therapeutic approaches in biomedicine.

Gene Polymorphisms and Drug-Drug Interactions Determine the Metabolic Profile of Blonanserin.

This study aimed to evaluate the effects of cytochrome P450 3A4 (CYP3A4) gene polymorphism and drug interaction on the metabolism of blonanserin. Human recombinant CYP3A4 was prepared using the Bac-to-Bac baculovirus expression system. A microsomal enzyme reaction system was established, and drug-drug interactions were evaluated using Sprague-Dawley rats. Ultra-performance liquid chromatography-tandem mass spectrometry was used to detect the concentrations of blonanserin and its metabolite. Compared with wild type CYP34A, the relative clearance of blonanserin by CYP3A4.29 significantly increased to 251.3%, while it decreased notably with CYP3A4.4, 5, 7, 8, 9, 10, 12, 13, 14, 16, 17, 18, 23, 24, 28, 31, 33, and 34, ranging from 6.09% to 63.34%. Among 153 tested drugs, nimodipine, felodipine, and amlodipine were found to potently inhibit the metabolism of blonanserin. Moreover, the inhibitory potency of nimodipine, felodipine, and amlodipine varied with different CYP3A4 variants. The half-maximal inhibitory concentration and enzymatic kinetics assay demonstrated that the metabolism of blonanserin was noncompetitively inhibited by nimodipine in rat liver microsomes and was inhibited in a mixed manner by felodipine and amlodipine in both rat liver microsomes and human liver microsomes. When nimodipine and felodipine were coadministered with blonanserin, the area under the blood concentration-time curve (AUC)(0-t), AUC(0-∞), and C max of blonanserin increased. When amlodipine and blonanserin were combined, the C max of blonanserin C increased remarkably. The vast majority of CYP3A4 variants have a low ability to catalyze blonanserin. With combined administration of nimodipine, felodipine, and amlodipine, the elimination of blonanserin was inhibited. This study provides the basis for individualized clinical use of blonanserin. SIGNIFICANCE STATEMENT: The enzyme kinetics of novel CYP3A4 enzymes for metabolizing blonanserin were investigated. Clearance of blonanserin by CYP3A4.4, 5, 7-10, 12-14, 16-18, 23-24, 28, 31, 33, and 34 decreased notably, but increased with CYP3A4.29. Additionally, we established a drug interaction spectrum for blonanserin, in which nimodipine, felodipine, and amlodipine kinetics exhibited mixed inhibition. Moreover, their inhibitory potencies decreased with CYP3A4.4 and 5 compared to CYP3A4.1. This study provides essential data for personalized clinical use of blonanserin.

Identifying the association between serum urate levels and gout flares in patients taking urate-lowering therapy: a post hoc cohort analysis of the CARES trial with consideration of dropout.

OBJECTIVE: To investigate gout flare rates based on repeated serum urate (SU) measurements in a randomised controlled trial of urate-lowering therapy (ULT), accounting for dropout and death. METHODS: We performed a secondary analysis using data from Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout, which randomised participants to febuxostat or allopurinol, titrated to target SU <6 mg/dL with flare prophylaxis for 6 months. SU was categorised as ≤3.9, 4.0-5.9, 6.0-7.9, 8.0-9.9 or ≥ 10 mg/dL at each 3-6 month follow-up. The primary outcome was gout flare. Poisson regression models, adjusted for covariates and factors related to participant retention versus dropout, estimated gout flare incidence rate ratios by time-varying SU category. RESULTS: Among 6183 participants, the median age was 65 years and 84% were male. Peak gout flare rates for all SU categories were observed in months 0-6, coinciding with the initiation of ULT and months 6-12 after stopping prophylaxis. Flare rates were similar across SU groups in the initial year of ULT. During months 36-72, a dose-response relationship was observed between the SU category and flare rate. Lower flare rates were observed when SU ≤3.9 mg/dL and greater rates when SU ≥10 mg/dL, compared with SU 4.0-5.9 mg/dL (p for trend <0.01). CONCLUSION: Gout flare rates were persistently higher when SU ≥6 mg/dL after the first year of ULT after accounting for censoring. The spike in flares in all categories after stopping prophylaxis suggests a longer duration of prophylaxis may be warranted.

Global burden of early-onset osteoarthritis, 1990-2019: results from the Global Burden of Disease Study 2019.

OBJECTIVES: Early-onset osteoarthritis (OA) is an emerging health issue amidst the escalating prevalence of overweight and obesity. However, there are scant data on its disease, economic burden and attributable burden due to high body mass index (BMI). METHODS: Using data from the Global Burden of Diseases Study 2019, we examined the numbers of incident cases, prevalent cases, years lived with disability (YLDs) and corresponding age-standardised rates for early-onset OA (diagnosis before age 55) from 1990 to 2019. The case definition was symptomatic and radiographically confirmed OA in any joint. The average annual percentage changes (AAPCs) of the age-standardised rates were calculated to quantify changes. We estimated the economic burden of early-onset OA and attributable burden to high BMI. RESULTS: From 1990 to 2019, the global incident cases, prevalent cases and YLDs of early-onset OA were doubled. 52.31% of incident OA cases in 2019 were under 55 years. The age-standardised rates of incidence, prevalence and YLDs increased globally and for countries in all Sociodemographic Index (SDI) quintiles (all AAPCs>0, p<0.05), with the fastest increases in low-middle SDI countries. 98.04% of countries exhibited increasing trends in all age-standardised rates. Early-onset OA accounts for US$46.17 billion in healthcare expenditure and US$60.70 billion in productivity loss cost in 2019. The attributable proportion of high BMI for early-onset OA increased globally from 9.41% (1990) to 15.29% (2019). CONCLUSIONS: Early-onset OA is a developing global health problem, causing substantial economic costs in most countries. Targeted implementation of cost-effective policies and preventive intervention is required to address the growing health challenge.

High-fat and high-sucrose diet impairs female reproduction by altering ovarian transcriptomic and metabolic signatures.

BACKGROUND: Excessive energy intake in modern society has led to an epidemic surge in metabolic diseases, such as obesity and type 2 diabetes, posing profound threats to women's reproductive health. However, the precise impact and underlying pathogenesis of energy excess on female reproduction remain unclear. METHODS: We established an obese and hyperglycemic female mouse model induced by a high-fat and high-sucrose (HFHS) diet, then reproductive phenotypes of these mice were evaluated by examing sexual hormones, estrous cycles, and ovarian morphologies. Transcriptomic and precise metabolomic analyses of the ovaries were performed to compare the molecular and metabolic changes in HFHS mice. Finally, orthogonal partial least squares discriminant analysis was performed to compare the similarities of traits between HFHS mice and women with polycystic ovary syndrome (PCOS). RESULTS: The HFHS mice displayed marked reproductive dysfunctions, including elevated serum testosterone and luteinizing hormone levels, irregular estrous cycles, and impaired folliculogenesis, mimicking the clinical manifestations of women with PCOS. Precise metabolomic overview suggested that HFHS diet disrupted amino acid metabolism in the ovaries of female mice. Additionally, transcriptional profiling revealed pronounced disturbances in ovarian steroid hormone biosynthesis and glucolipid metabolism in HFHS mice. Further multi-omics analyses unveiled prominent aberration in ovarian arginine biosynthesis pathway. Notably, comparisons between HFHS mice and a cohort of PCOS patients identified analogous reproductive and metabolic signatures. CONCLUSIONS: Our results provide direct in vivo evidence for the detrimental effects of overnutrition on female reproduction and offer insights into the metabolic underpinnings of PCOS.

The mediation effects of malalignment on the relation of sex to the risk of incidence tibiofemoral osteoarthritis.

OBJECTIVE: To investigate to what extent the higher risk of tibiofemoral radiographic osteoarthritis (TFROA) in females vs. males can be explained by knee malalignment. DESIGN: Using data from Multicenter Osteoarthritis Study (MOST) and Osteoarthritis Initiative (OAI), we examined the relation of sex to the incident medial and lateral TFROA and performed mediation analyses to assess to what extent varus and valgus malalignments account for sex differences in the incident medial or lateral TFROA. RESULTS: Of the 3462 knees without medial and lateral TFROA in MOST, the 7-year risks of medial and lateral TFROA were 16.9% and 10.0% in females, and 15.8% and 4.2% in males, respectively. Females had 2.31-fold (95% confidence interval [95% CI]: 1.73 to 3.08) higher incident lateral TFROA than males, and the relative risk (RR) of the indirect effect of sex on lateral TFROA through valgus malalignment was 1.15 (95% CI: 1.09 to 1.20), accounting for 23% of its total effect on lateral TFROA. In OAI (n = 3095 knees), females had 1.54-fold (95% CI: 1.15 to 2.04) higher incident lateral TFROA than males, and RR of the indirect effect of sex on lateral TFROA through valgus malalignment was 1.10 (95% CI: 1.04 to 1.21), accounting for 26% of its total effect on lateral TFROA. No apparent sex difference in the incident medial TFROA was found in MOST (RR = 1.05, 95% CI: 0.89 to 1.25) or OAI (RR = 1.02, 95% CI: 0.84 to 1.19). CONCLUSION: Females had a higher risk of developing lateral TFROA than males; however, valgus malalignment only modestly explained such a difference.

The clinical outcomes and healthcare resource utilization in IgG4-related disease: a claims-based analysis of commercially insured adults in the United States.

OBJECTIVES: IgG4-related disease (IgG4-RD) can affect nearly any organ and is often treated with glucocorticoids, which contribute to organ damage and toxicity. Comorbidities and healthcare utilization in IgG4-RD are poorly understood. METHODS: We conducted a cohort study using claims data from a United States managed care organization. Incident IgG4-RD cases were identified using a validated algorithm; general population comparators were matched by age, sex, race/ethnicity, and index date. The frequency of 21 expert-defined clinical outcomes associated with IgG4-RD or its treatment and healthcare-associated visits and costs were assessed 12 months before and 36 months after the index date (date of earliest IgG4-RD-related claim). RESULTS: There were 524 cases and 5,240 comparators. Most cases received glucocorticoids prior to (64.0%) and after (85.1%) the index date. Nearly all outcomes, many being common glucocorticoid toxicities, occurred more frequently in cases vs comparators. During follow-up, the largest differences between cases and comparators were seen for gastroesophageal reflux disease (prevalence difference: +31.2%, p< 0.001); infections (+17.3%, p< 0.001); hypertension (+15.5%, p< 0.01); and diabetes mellitus (+15.0%, p< 0.001). The difference in malignancy increased during follow-up from +8.8% to + 12.5% (p< 0.001). 17.4% of cases used pancreatic enzyme replacement therapy during follow-up. Over follow-up, cases were more often hospitalized (57.3% vs 17.2%, p< 0.01) and/or had an ER visit (72.0% vs 36.7%, p< 0.01); all costs were greater in cases than comparators. CONCLUSIONS: Patients with IgG4-RD are disproportionately affected by adverse outcomes, some of which may be preventable or modifiable with vigilant clinician monitoring. Glucocorticoid-sparing treatments may improve these outcomes.

Effects of different light conditions on morphological, anatomical, photosynthetic and biochemical parameters of Cypripedium macranthos Sw.

In this study, the morphological (plant height, leaf length and width, stem diameter and leaf number), anatomical (epidermal cell density and thickness, Stomatal length and width), photosynthetic (net photosynthetic rate, transpiration rate, stomatal conductance, intercellular CO2 concentration, relative humidity, leaf temperature and chlorophyll fluorescence parameters) and biochemical parameters (the content of soluble sugar, soluble protein, proline, malondialdehyde and electrical conductivity) of Cypripedium macranthos Sw. in Changbai Mountain were determined under different light conditions (L10, L30, L50, L100). The results showed that morphological values including plant height, leaf area, stem diameter and leaf number of C. macranthos were smaller under the condition of full light at L100. The epidermal cell density and epidermal thickness of C. macranthos were the highest under L30 and L50 treatments, respectively. It had the highest net photosynthetic rate (Pn) and chlorophyll content under L50 treatment. Meanwhile, correlation analysis indicated that photosynthetically active radiation (PAR) and water use efficiency (WUE) were the main factors influencing Pn. C. macranthos accumulated more soluble sugars and soluble proteins under L100 treatment, while the degree of membrane peroxidation was the highest and the plant was severely damaged. In summary, the adaptability of C. macranthos to light conditions is ranked as follows L50 > L30 > L10 > L100. Appropriate light conditions for C. macranthos are 30%-50% of full light, which should be taken into account in protection and cultivation.

Lysosome-targeted ruthenium(II) complex encapsulated with pluronic® F-127 induces oncosis in A549 cells.

Transition metal complexes with characteristics of unique packaging in nanoparticles and remarkable cancer cell cytotoxicity have emerged as potential alternatives to platinum-based antitumor drugs. Here we report the synthesis, characterization, and antitumor activities of three new Ruthenium complexes that introduce 5-fluorouracil-derived ligands. Notably, encapsulation of one such metal complex, Ru3, within pluronic® F-127 micelles (Ru3-M) significantly enhanced Ru3 cytotoxicity toward A549 cells by a factor of four. To determine the mechanisms underlying Ru3-M cytotoxicity, additional in vitro experiments were conducted that revealed A549 cell treatment with lysosome-targeting Ru3-M triggered oxidative stress, induced mitochondrial membrane potential depolarization, and drastically reduced intracellular ATP levels. Taken together, these results demonstrated that Ru3-M killed cells mainly via a non-apoptotic pathway known as oncosis, as evidenced by observed Ru3-M-induced cellular morphological changes including cytosolic flushing, cell swelling, and cytoplasmic vacuolation. In turn, these changes together caused cytoskeletal collapse and activation of porimin and calpain1 proteins with known oncotic functions that distinguished this oncotic process from other cell death processes. In summary, Ru3-M is a potential anticancer agent that kills A549 cells via a novel mechanism involving Ru(II) complex triggering of cell death via oncosis.

RORα inhibits gastric cancer proliferation through attenuating G6PD and PFKFB3 induced glycolytic activity.

BACKGROUND: Glycolysis is critical for harvesting abundant energy to maintain the tumor microenvironment in malignant tumors. Retinoic acid-related orphan receptor α (RORα) has been identified as a circadian gene. However, the association of glycolysis with RORα in regulating gastric cancer (GC) proliferation remains poorly understood. METHODS: Bioinformatic analysis and retrospective study were utilized to explore the role of RORα in cell cycle and glycolysis in GC. The mechanisms were performed in vitro and in vivo including colony formation, Cell Counting Kit-8 (CCK-8), Epithelial- mesenchymal transition (EMT) and subcutaneous tumors of mice model assays. The key drives between RORα and glycolysis were verified through western blot and chip assays. Moreover, we constructed models of high proliferation and high glucose environments to verify a negative feedback and chemoresistance through a series of functional experiments in vitro and in vivo. RESULTS: RORα was found to be involved in the cell cycle and glycolysis through a gene set enrichment analysis (GSEA) algorithm. GC patients with low RORα expression were not only associated with high circulating tumor cells (CTC) and high vascular endothelial growth factor (VEGF) levels. However, it also presented a positive correlation with the standard uptake value (SUV) level. Moreover, the SUVmax levels showed a positive linear relation with CTC and VEGF levels. In addition, RORα expression levels were associated with glucose 6 phosphate dehydrogenase (G6PD) and phosphofructokinase-2/fructose-2,6-bisphosphatase (PFKFB3) expression levels, and GC patients with low RORα and high G6PD or low RORα and high PFKFB3 expression patterns had poorest disease-free survival (DFS). Functionally, RORα deletion promoted GC proliferation and drove glycolysis in vitro and in vivo. These phenomena were reversed by the RORα activator SR1078. Moreover, RORα deletion promoted GC proliferation through attenuating G6PD and PFKFB3 induced glycolytic activity in vitro and in vivo. Mechanistically, RORα was recruited to the G6PD and PFKFB3 promoters to modulate their transcription. Next, high proliferation and high glucose inhibited RORα expression, which indicated that negative feedback exists in GC. Moreover, RORα deletion improved fluorouracil chemoresistance through inhibition of glucose uptake. CONCLUSION: RORα might be a novel biomarker and therapeutic target for GC through attenuating glycolysis.

Melatonin is a potential novel analgesic agent for osteoarthritis: Evidence from cohort studies in humans and preclinical research in rats.

Melatonin exhibits potential for pain relief and long-term safety profile. We examined the analgesic effects of oral melatonin on osteoarthritis (OA) and investigated the underlying mechanism. Using data from a UK primary care database, we conducted a cohort study in individuals with OA to compare the number of oral analgesic prescriptions and the risk of knee/hip replacement between melatonin initiators and hypnotic benzodiazepines (i.e., active comparator) initiators using quantile regression models and Cox-proportional hazard models, respectively. To elucidate causation, we examined the effects of melatonin on pain behaviors and explored several metabolites that may serve as potential regulatory agents of melatonin in the monoiodoacetate rat model of OA. Using data from another community-based cohort study, that is, the Xiangya OA Study, we verified the association between the key serum metabolite and incident symptomatic knee OA. Compared with the hypnotic benzodiazepines cohort (n = 8135), the melatonin cohort (n = 813) had significantly fewer subsequent prescriptions of oral analgesics (50th percentile: 5 vs. 7, 75th percentile: 19 vs. 29, and 99th percentile: 140 vs. 162) and experienced a lower risk of knee/hip replacement (hazard ratio = 0.47, 95% Cl: 0.30-0.73) during the follow-up period. In rats, oral melatonin alleviated pain behaviors and increased serum levels of glycine. There was an inverse association between baseline serum glycine levels and the risk of incident symptomatic knee OA in humans (n = 760). In conclusion, our findings indicate that oral melatonin shows significant potential to be a novel treatment for OA pain. The potential role of glycine in its analgesic mechanism warrants further investigation.

7,8-dihydroxyflavone displayed antioxidant effect through activating HO-1 expression and inhibiting caspase-3/PARP activation in RAW264.7 cells.

Flavonoids, which contain a benzo-γ-pyrone (C6-C3-C6) skeleton, have been reported to exhibit effective antioxidant ability. This study aimed to compare the antioxidant activities of 7,8-dihydroxyflavone (7,8-DHF) and 7-hydroxyflavone (7-HF) in H2 O2 , lipopolysaccharide (LPS), or tert-butyl hydroperoxide (t-BHP)-induced RAW264.7 cells, respectively. The antioxidant capacities of 7,8-DHF and 7-HF were firstly evaluated by 2,2-azinobis-3-ethyl-benzothiazoline-6-sulphonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. Then, reactive oxygen species (ROS), super oxide dismutase (SOD), and malondialdehyde (MDA) productions in H2 O2 , LPS, or t-BHP-induced RAW264.7 cells were tested and compared, respectively. Finally, the antioxidant mechanisms of 7-HF and 7,8-DHF were initially investigated by western blot. Our results showed that 7,8-DHF possessed stronger free-radical scavenging capacity than 7-HF. Both 7,8-DHF and 7-HF suppressed MDA production and ROS accumulation, improved the activity of SOD in H2 O2 , LPS, or t-BHP-induced RAW264.7 cells, respectively. And 7,8-DHF exerted a better antioxidant effect than 7-HF, especially in t-BHP-induced oxidative stress. Mechanically, 7,8-DHF prevented the activation of poly ADP-ribosepolymerase and caspase-3, meanwhile markedly upregulated the expression of HO-1 protein in t-BHP-induced oxidative stress. These results suggested that 7,8-DHF might serve as a potential pharmaceutical drug against oxidative stress injury.

Disassociation between fluctuation shift over frequency and glucose metabolism in motor cortex of Parkinson's disease: a hybrid PET/fMRI study.

Increased glucose metabolism and decreased low-frequency fluctuation have been consistently reported in the motor area of Parkinson's disease (PD). The reason for such seeming paradox is unclear. Here, we enrolled 34 PD patients and 25 healthy controls (HCs) for hybrid PET/fMRI scan (PET/fMRI(discovery) dataset). In addition, 2 replication datasets, namely fMRI(validation-1) and fMRI(validation-2) dataset, were also included. We computed ratio of standard uptake value (SUVr) to measure FDG-uptake. The amplitude of low-frequency fluctuations (ALFF) for the following 4 frequency bands was calculated: slow-5, slow-4, slow-3, and slow-2. We obtained a significant group-by-frequency interaction effect of ALFF in the paracentral lobule/supplementary motor area (PFWE = 0.003) and the right sensorimotor area (PFWE < 0.001) in the PET/fMRI(discovery) dataset, which could be replicated using fMRI(validation-1) and fMRI(validation-2) datasets (PFWE < 0.05). In detail, HCs exhibited power law-like fluctuation pattern, but PD patients did not. Correlation analyses further revealed significant associations between ALFF and FDG-uptake in HCs (P-values < 0.031), but not in PD (P-values > 0.28). Taken together, this study identified a fluctuation shift over frequency effect in PD patients, which further disassociated with glucose metabolism in the motor cortex.