Ultrasensitive Fluorescent Microsensors Based on Aptamers Modified with SYBR Green I for Visual Quantitative Detection of Organophosphate Pesticides.

Organophosphate pesticides (OPs) are widely utilized in agricultural production, and the residues threaten public health and environmental safety due to their toxicity. Herein, a novel and simple DNA aptamer-based sensor has been fabricated for the rapid, visual, and quantitative detection of profenofos and isocarbophos. The proposed DNA aptamers with a G-quadruplex spatial structure could be recognized by SYBR Green I (SG-I), resulting in strong green fluorescence emitted by SG-I. The DNA aptamers exhibit a higher specific binding ability to target OP molecules through aromatic ring stacking, disrupting the interaction between SG-I and DNA aptamers to induce green fluorescence quenching. Meanwhile, the fluorescence wavelength of G-quadruplex fluorescence emission peaks changes, accompanied by an obvious fluorescence variation from green to blue. SG-I-modified aptasensor without any additive reference fluorescence units for use in multicolor fluorescence assay for selective monitoring of OPs was first developed. The developed aptasensor provides a favorable linear range from 0 to 200 nM, with a low detection limit of 2.48 and 3.01 nM for profenofos and isocarbophos, respectively. Moreover, it offers high selectivity and stability in real sample detection with high recoveries. Then, a self-designed portable smartphone sensing platform was successfully used for quantitative result outputs, demonstrating experience in designing a neotype sensing strategy for point-of-care pesticide monitoring.

UFM1 inhibits hypoxia-induced angiogenesis via promoting proteasome degradation of HIF-1α.

Angiogenesis is crucial for blood flow recovery and ischemic tissue repair of peripheral artery disease (PAD). Exploration of new mechanisms underlying angiogenesis will shed light on the treatment of PAD. Ubiquitin-fold modifier 1 (UFM1), a newly identified ubiquitin-like molecule, has been discovered to be involved in various pathophysiological processes. However, the role of UFM1 in the pathogenesis of PAD, especially in endothelial angiogenesis remains obscure, and we aimed to clarify this issue in this study. We initially found UFM1 was significantly upregulated in gastrocnemius muscles of PAD patients and hind limb ischemia mice. And UFM1 was mainly colocalized with endothelial cells in ischemic muscle tissues. Further, elevated expression of UFM1 was observed in hypoxic endothelial cells. Subsequent genetic inhibition of UFM1 dramatically enhanced migration, invasion, adhesion, and tube formation of endothelial cells under hypoxia. Mechanistically, UFM1 reduced the stability of hypoxia-inducible factor-1α (HIF-1α) and promoted the von Hippel-Lindau-mediated K48-linked ubiquitin-proteasome degradation of HIF-1α, which in turn decreased angiogenic factor VEGFA expression and suppressed VEGFA related signaling pathway. Consistently, overexpression of UFM1 inhibited the angiogenesis of endothelial cells under hypoxic conditions, whereas overexpression of HIF-1α reversed this effect. Collectively, our data reveal that UFM1 inhibits the angiogenesis of endothelial cells under hypoxia through promoting ubiquitin-proteasome degradation of HIF-1α, suggesting UFM1 might serve as a potential therapeutic target for PAD.

Thermal ablation for the treatment of malignant thyroid nodules: present and future.

As the utilization of high-resolution imaging modalities, such as ultrasound, becomes increasingly prevalent, there has been a swift rise in the detection rates of malignant thyroid nodules (MTC). Surgery remains the cornerstone of standard treatment for these nodules. However, the advent and evolution of thermal ablation (TA) techniques, encompassing radiofrequency ablation, laser ablation, and microwave ablation, have emerged as a novel therapeutic avenue for patients with MTC, particularly for those deemed unsuitable for surgery due to high risks or for those who refuse surgery. Presently, TA has been validated as an efficacious and safe intervention for both benign thyroid nodules and a subset of MTC. An expanding body of research has been dedicated to broadening the applicability of TA, initially from recurrent thyroid cancer and lymph nodes to now encompass isolated papillary thyroid microcarcinomas (PTMC) alongside a comprehensive exploration into the expanded parameters such as size, number, and location of PTMC, and its applicability in other types of thyroid cancer. This review provides a detailed synthesis of the clinical evidence about the use of TA in the management of MTC, as endorsed by current guidelines. It further delves into the ongoing research efforts aimed at extending its indications and discusses the prospective implications and challenges of integrating TA into the clinical management paradigms for MTC.

New natural protein tyrosine phosphatase 1B inhibitors from Gynostemma pentaphyllum.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease mainly caused by insulin resistance, which can lead to a series of complications such as cardiovascular disease, retinopathy, and its typical clinical symptom is hyperglycaemia. Glucosidase inhibitors, including Acarbose, Miglitol, are commonly used in the clinical treatment of hypoglycaemia. In addition, Protein tyrosine phosphatase 1B (PTP1B) is also an important promising target for the treatment of T2DM. Gynostemma pentaphyllum is a well-known oriental traditional medicinal herbal plant, and has many beneficial effects on glucose and lipid metabolism. In the present study, three new and nine known dammarane triterpenoids isolated from G. pentaphyllum, and their structures were elucidated by spectroscopic methods including HR-ESI-MS,1H and 13C NMR and X-ray crystallography. All these compounds were evaluated for inhibitory activity against α-glucosidase, α-amylase and PTP1B. The results suggested that compounds 7∼10 were potential antidiabetic agents with significantly inhibition activity against PTP1B in a dose-dependent manner.

Substantial accumulation of mercury in the deepest parts of the ocean and implications for the environmental mercury cycle.

Anthropogenic activities have led to widespread contamination with mercury (Hg), a potent neurotoxin that bioaccumulates through food webs. Recent models estimated that, presently, 200 to 600 t of Hg is sequestered annually in deep-sea sediments, approximately doubling since industrialization. However, most studies did not extend to the hadal zone (6,000- to 11,000-m depth), the deepest ocean realm. Here, we report on measurements of Hg and related parameters in sediment cores from four trench regions (1,560 to 10,840 m), showing that the world's deepest ocean realm is accumulating Hg at remarkably high rates (depth-integrated minimum-maximum: 24 to 220 µg ⋅ m-2 ⋅ y-1) greater than the global deep-sea average by a factor of up to 400, with most Hg in these trenches being derived from the surface ocean. Furthermore, vertical profiles of Hg concentrations in trench cores show notable increasing trends from pre-1900 [average 51 ± 14 (1σ) ng ⋅ g-1] to post-1950 (81 ± 32 ng ⋅ g-1). This increase cannot be explained by changes in the delivery rate of organic carbon alone but also need increasing Hg delivery from anthropogenic sources. This evidence, along with recent findings on the high abundance of methylmercury in hadal biota [R. Sun et al, Nat. Commun. 11, 3389 (2020); J. D. Blum et al, Proc. Natl. Acad. Sci. U. S. A. 117, 29292-29298 (2020)], leads us to propose that hadal trenches are a large marine sink for Hg and may play an important role in the regulation of the global biogeochemical cycle of Hg.

The current landscape of coumarin hybrids with antibreast cancer therapeutic applications: An updated review.

Globally, breast cancer (BC) has the highest prevalence among malignant diseases. BC is also the primary cause of death among women. Notably, BC morbidity has been increasing continuously at an approximate growth rate of 2.2% per year. Persistent BC is a major public health issue worldwide. Consequently, novel chemotherapeutic agents to combat this lethal disease should be developed urgently. Coumarins with interesting structural and mechanistic variations exhibit promising activity in several forms of BC, including BCs with multidrug resistance. In particular, coumarin hybrids composed of coumarin and one or more anti-BC pharmacophores can target different biological components in BC cells simultaneously. Thus, coumarin hybrids are useful scaffolds that can help improve the anti-BC efficacy of coumarins, reduce side effects, improve pharmacokinetics, minimize drug-drug interactions, and circumvent drug resistance. This review, in which articles published from 2020 to the present day have been evaluated, highlights the landscape of coumarin hybrids that exhibit therapeutic effects against breast cancer. These findings can aid further investigations on novel antibreast-cancer therapeutics.

Current scenario of chalcone hybrids with antibreast cancer therapeutic applications.

Breast cancer, an epithelial malignant tumor that occurs in the terminal ducts of the breast, is the most common female malignancy. Currently, approximately 70%-80% of breast cancer with early-stage, nonmetastatic disorder is curable, but the emergency of drug resistance often leads to treatment failure. Moreover, advanced breast cancer with distant organ metastases is incurable with the available therapeutics, creating an urgent demand to explore novel antibreast cancer agents. Chalcones, the precursors for flavonoids and isoflavonoids, exhibit promising activity against various breast cancer hallmarks, inclusive of proliferation, angiogenesis, invasion, metastasis, inflammation, stemness, and regulation of cancer epigenetics, representing useful scaffolds for the discovery of novel antibreast cancer chemotherapeutic candidates. In particular, chalcone hybrids could act on two or more different biological targets simultaneously with more efficacy, lower toxicity, and less susceptibility to resistance. Accordingly, there is a huge scope for application of chalcone hybrids to tackle the present difficulties in breast cancer therapy. This review outlines the chalcone hybrids with antibreast cancer potential developed from 2018. The structure-activity relationships as well as mechanisms of action are also discussed to shed light on the development of more effective and multitargeted chalcone candidates.

Photoinduced Electron Transfer-Triggered g-C3N4\Rhodamine B Sensing System for the Ratiometric Fluorescence Quantitation of Carbendazim.

Assays for carbendazim (Car) with high sensitivity and on-site screening have been urgently required to protect the ecosystem and prevent disease. In this work, a simple, sensitive, and reliable sensing system based on photoinduced electron transfer was established to detect carbendazim utilizing ultrathin graphitic carbon nitride (g-C3N4) nanosheets and rhodamine B (RB). Carbendazim reacts with g-C3N4 by electrostatic interactions to form π-π stacking, and the quenching of the blue fluorescence is caused by electron transfer. While RB works as a reference fluorescence sensor without any fluorescence change, leading to obvious ratiometric fluorescence variation from blue to purple. Under optimal conditions, a favorable linear range from 20 to 180 nM was obtained, with a low detection limit of 5.89 nM. In addition, a portable smartphone sensing platform was successfully used for carbendazim detection in real samples with excellent anti-interference capability, demonstrating the potential applications of carbendazim monitoring.

Filamin A is overexpressed in non-alcoholic steatohepatitis and contributes to the progression of inflammation and fibrosis.

Non-alcoholic steatohepatitis (NASH) is a chronic and progressive liver disease characterized by steatosis, inflammation, and fibrosis. Filamin A (FLNA), an actin-binding protein, is involved in various cell functions, including the regulation of immune cells and fibroblasts. However, its role in the development of NASH through inflammation and fibrogenesis is not fully understood. In this study, we found that FLNA expression was increased in liver tissues of patients with cirrhosis and mice with non-alcoholic fatty liver disease (NAFLD)/NASH and fibrosis. Immunofluorescence analysis showed that FLNA was primarily expressed in macrophages and hepatic stellate cells (HSCs). Knocking down of FLNA by specific shRNA in phorbol-12-myristate-13-acetate (PMA)-derived THP-1 macrophages reduced lipopolysaccharide (LPS)-stimulated inflammatory response. The decreased mRNA levels of inflammatory cytokines and chemokines and suppression of the STAT3 signaling were observed in FLNA-downregulated macrophages. In addition, knockdown of FLNA in immortalized human hepatic stellate cells (LX-2 cells) resulted in decreased mRNA levels of fibrotic cytokines and enzymes involved in collagen synthesis, as well as increased levels of metalloproteinases and pro-apoptotic proteins. Overall, these results suggest that FLNA may contribute to the pathogenesis of NASH through its role in the regulation of inflammatory and fibrotic mediators.

A three-snoRNA signature: SNORD15A, SNORD35B and SNORD60 as novel biomarker for renal cell carcinoma.

BACKGROUND: Accumulating evidence has confirmed the role of snoRNAs in a variety of cancer, but rare in renal cell carcinoma (RCC). This study aims to clarify the role of snoRNAs in RCC tumorigenesis and their potential as novel tumor biomarkers. MATERIALS AND METHODS: The snoRNA expression matrix was obtained from the public TCGA and SNORic databases. SNORD15A, SNORD35B and SNORD60 were selected and validated by qPCR, then analyzed combined with related clinical factors using T-test and ROC curve. RESULTS: All three snoRNAs: SNORD15A, SNORD35B and SNORD60 were significantly upregulated in cancer tissues compared to adjacent tissues from TCGA or FFPE detection. These three snoRNAs were also increased in urinary sediment (US) of RCC as well as the early-stage RCC patients compared with the healthy controls. In addition, RNase stability experiments confirmed their stable existence in US. Meanwhile, the ROC curve shows that SNORD15A, SNORD35B and SNORD60 could effectively distinguish RCC (AUC = 0.7421) and early-stage RCC (AUC = 0.7465) from healthy individuals. CONCLUSION: SNORD15A, SNORD35B and SNORD60 were upregulated in tissues and US of RCC, serving as novel potential biomarkers for RCC diagnosis.

Wintertime Formation of Large Sulfate Particles in China and Implications for Human Health.

Outdoor air pollution causes millions of premature deaths annually worldwide. Sulfate is a major component of particulate pollution. Winter sulfate observations in China show both high concentrations and an accumulation mode with a modal size >1 µm. However, we find that this observed size distribution cannot be simulated using classical gaseous and aqueous phase formation (CSF) or proposed aerosol-processing formation (APF) mechanisms. Specifically, the CSF simulation underestimates sulfate concentrations by 76% over megacities in China and predicts particle size distributions with a modal size of ∼0.35 µm, significantly smaller than observations. Although incorporating the APF mechanism in the atmospheric chemical model notably improves sulfate concentration simulation with reasonable parameters, the simulated sulfate particle size distribution remains similar to that using the CSF mechanism. We further conduct theoretical analyses and show that particles with diameters <0.3 µm grow rapidly (2-3 s) to 1 µm through the condensation of sulfuric acid in fresh high-temperature exhaust plumes, referred to as in-source formation (ISF). An ISF sulfate source equivalent to 15% of sulfur emissions from fossil fuel combustion largely explains both observed size distributions and mass concentrations of sulfate particles. The findings imply that ISF is a major source of wintertime micron-sized sulfate in China and underscore the importance of considering the size distribution of aerosols for accurately assessing the impacts of inorganic aerosols on radiative forcing and human health.

Riverine Discharge Fuels the Production of Methylmercury in a Large Temperate Estuary.

Estuaries are an important food source for the world's growing population, yet human health is at risk from elevated exposure to methylmercury (MeHg) via the consumption of estuarine fish. Moreover, the sources and cycling of MeHg in temperate estuarine ecosystems are poorly understood. Here, we investigated the seasonal and tidal patterns of mercury (Hg) forms in Long Island Sound (LIS), in a location where North Atlantic Ocean waters mix with the Connecticut River. We found that seasonal variations in Hg and MeHg in LIS followed the extent of riverine Hg delivery, while tides further exacerbated the remobilization of earlier deposited riverine Hg. The net production of MeHg near the river plume was significant compared to that in other locations and enhanced during high tide, possibly resulting from the enhanced microbial activity and organic carbon remineralization in the river plume. Statistical models, driven by our novel data, further support the hypothesis that the river-delivered organic matter and inorganic Hg drive net MeHg production in the estuarine water column. Our study sheds light on the significance of water column biogeochemical processes in temperate tidal estuaries in regulating MeHg levels and inspires new questions in our quest to understand MeHg sources and dynamics in coastal oceans.

Large-Scale Observations Support Aboveground Vegetation as an Important Biological Mercury Sink in the Tibetan Plateau.

Mercury, a pervasive global pollutant, primarily enters the atmosphere through human activities and legacy emissions from the land and oceans. A significant portion of this mercury subsequently settles on land through vegetation uptake. Characterizing mercury storage and distribution within vegetation is essential for comprehending regional and global mercury cycles. We conducted an unprecedented large-scale aboveground vegetation mercury survey across the expansive Tibetan Plateau. We find that mosses (31.1 ± 0.5 ng/g) and cushion plants (15.2 ± 0.7 ng/g) outstood high mercury concentrations. Despite exceptionally low anthropogenic mercury emissions, mercury concentrations of all biomes exceeded at least one-third of their respective global averages. While acknowledging the role of plant physiological factors, statistical models emphasize the predominant impact of atmospheric mercury on driving variations in mercury concentrations. Our estimations indicate that aboveground vegetation on the plateau accumulates 32-12+21 Mg (interquartile range) mercury. Forests occupy the highest biomass and store 82% of mercury, while mosses, representing only 3% of the biomass, disproportionally contribute 13% to mercury storage and account for 43% (2.5-1.4+3.0 Mg/year) of annual mercury assimilation by vegetation. Additionally, our study underscores that extrapolating aboveground vegetation mercury storage from lower-altitude regions to the Tibetan Plateau can lead to substantial overestimation, inspiring further exploration in alpine ecosystems worldwide.

Tumor-educated platelet SNORA58, SNORA68 and SNORD93 as novel diagnostic biomarkers for esophageal cancer.

Aim: The purpose of this study was to evaluate whether tumor-educated platelet (TEP) snoRNAs could be used as a diagnostic biomarker for esophageal cancer (ESCA). Methods: Platelet precipitates were obtained from platelet-rich plasma by low-speed centrifugation, and total RNA was extracted from platelets using Trizol™ reagent. RT-qPCR was used to detect snoRNA expression, and the receiver operating characteristic was used to assess its diagnostic potential. Results: SNORA58, SNORA68 and SNORD93 were significantly upregulated in TEPs from ESCA patients and early-stage patients compared with healthy controls. Importantly, the three snoRNAs were capable of serving as circulating biomarkers of diagnostics and early diagnosis of ESCA, possessing areas under the curve of 0.846 and 0.857, respectively. Conclusion: TEP SNORA58, SNORA68 and SNORD93 could potentially serve as noninvasive biomarkers for diagnosis and early diagnosis of ESCA.

New dammarane-type triterpenoids from hydrolyzate of total Gynostemma pentaphyllum saponins with protein tyrosine phosphatase 1B inhibitory activity.

Protein tyrosine phosphatase 1B (PTP1B) is a key factor and regulator of glucose, lipid metabolism throughout the body, and a promising target for treatment of type 2 diabetes mellitus (T2DM). Gynostemma pentaphyllum is a famous oriental traditional medicinal herbal plant and functional food, which has shown many beneficial effects on glucose and lipid metabolism. The aim of the present study is to assess the inhibitory activity of five new and four known dammarane triterpenoids isolated from the hydrolysate product of total G. pentaphyllum saponins. The bioassay data showed that all the compounds exhibited significant inhibitory activity against PTP1B. The structure-activity relationship showed that the strength of PTP1B inhibitory activity was mainly related to the electron-donating group on its side chain. Molecular docking analysis suggested that its mechanism may be due to the formation of competitive hydrogen bonding between the electron-donating moiety and the Asp48 amino acid residues on the PTP1B protein.

Widely Targeted Metabolomics Analysis of Dendrobium officinale at Different Altitudes.

In order to investigate the differences in the chemical composition of Dendrobium officinale at different altitudes, we collected Dendrobium officinale from different altitudes in Guizhou Province, China, and firstly determined its polysaccharide content by using a sulfuric acid-phenol color development method with reference to the Chinese Pharmacopoeia, and further determined its metabolites by using widely targeted metabolomics, and explored the differences in the chemical composition of Dendrobium officinale at different altitudes using multivariate statistical analysis. We found that the polysaccharide content was higher in plants growing at 1122 m, a total of 902 secondary metabolites were detected by wildly targeted metabolomics, and amino acids and their derivatives were more highly expressed at 1122 m, while other metabolites were more highly expressed at 835 m. Furthermore, we found that the phenolic acid compound nerugein was only present in plants at 835 m, and two lipid compounds, namely Lyso PE 20 : 4 and its isomer, were only present at 1122 m. Taken together, these results may provide a basis for the selection and clinical application of D. officinale cultivated at different altitudes.

Artemisinin-isatin hybrids tethered via ethylene linker and their anti-lung cancer activity.

The synthesized 11 artemisinin-isatin hybrids 5a-c and 6a-h tethered via ethylene linker were assessed for their in vitro antiproliferative activity against A549 and H1299 nonsmall-cell lung cancer cell lines as well as their cytotoxicity towards BEAS-2B human normal lung epithelial cells. The preliminary results showed that hybrids 5a-c and 6a-h did not show any cytotoxicity (IC50 : >100 µM) on BEAS-2B cells, and also possessed potential activity (IC50 : 6.99-76.49 µM) against A549 and H1299 lung cancer cell lines. The representative hybrid 6c (IC50 : 6.99 and 7.57 µM) was far more potent than artemisinin (IC50 : >100 µM) and dihydroartemisinin (IC50 : >100 µM), and was slightly less active than doxorubicin (IC50 : 4.14 and 2.77 µM). Moreover, hybrid 6c also exhibited an excellent safety profile and good selectivity with SI values of >13.21. Therefore, hybrid 6c could serve as a promising candidate for further in vivo evaluations.

Aromatic diglycosides from Sophora tonkinensis and a multi-step conformer filtering procedure for TDDFT calculation of flexible glycoside.

Three previously undescribed aromatic diglycosides (1, 5, and 8) and six known analogs (2-4, 6, 7, and 9) were isolated from the roots and rhizomes of Sophora tonkinensis Gagnep. Their structures were elucidated by detailed spectroscopic analysis. The absolute configuration of compound 8 was determined by comparing the experimental and TDDFT calculated ECD spectra of 8 and aglycone 8a. Furthermore, a multistep conformer filtering procedure for TDDFT calculation of flexible glycoside was proposed, which afforded high accuracy with acceptable computing cost in determining the absolute configuration of glycosides using quantum calculated ECD.

Research Progress of Takeda G Protein-Coupled Receptor 5 in Metabolic Syndrome.

Bile acids are acknowledged as signaling molecules involved in metabolic syndrome. The Takeda G protein-coupled receptor 5 (TGR5) functions as a significant bile acid receptor. The accumulated evidence suggests that TGR5 involves lipid homeostasis, glucose metabolism, and inflammation regulation. In line with this, recent preclinical studies also demonstrate that TGR5 plays a significant role in the generation and progression of metabolic syndrome, encompassing type 2 diabetes mellitus, obesity, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). In this review, we discuss the role of TGR5 in metabolic syndrome, illustrating the underlying mechanisms and therapeutic targets.

Rapid Increase in China's Industrial Ammonia Emissions: Evidence from Unit-Based Mapping.

Ammonia (NH3) is an important precursor of secondary inorganic aerosols and greatly impacts nitrogen deposition and acid rain. Previous studies have mainly focused on the agricultural NH3 emissions, while recent research has noted that industrial sources could be significant in China. However, detailed estimates of NH3 emitted from industrial sectors in China are lacking. Here, we established an unprecedented high-spatial-resolution data set of China's industrial NH3 emissions using up-to-date measurements of NH3 and point source-level information covering eight major industries and 27 subdivided process categories. We found that China emitted 798 (90% confidence interval: 668-933) gigagrams of industrial NH3 into the atmosphere in 2019, equivalent to 44 ± 20% of the industrial emissions worldwide; this flux is 3-fold larger than that in 1998 and has fluctuated since 2014. Furthermore, although fertilizer production is responsible for approximately half of the emissions in China, the emissions from cement production and coal-fired power plants increased dramatically from near zero to 164 and 41 gigagrams, respectively, in the past two decades, primarily due to the NH3 escape caused by the large-scale application of the denitration process. Our results reveal that, unlike other major air pollutants, China's industrial NH3 emission control is still in a critical period, and stricter NH3 emission standards and innovation in pollution control technologies are highly desirable.