Lysosome-Targeted Polarity-Sensitive NIR Fluorescence Probe for Imaging Injured Lung and Liver in Diabetes.

Diabetes is a chronic disease marked by high blood glucose. With the progress of diabetes, complications gradually appear, and various organs may be affected. However, due to the lack of noninvasive in situ detection probes, the diagnosis of organ damage caused by diabetes is significantly delayed, which will cause many complications that cannot be treated in time. Here, we report a BODIPY-based fluorescent probe SNL, which can be used to detect lung and liver damage caused by diabetes. By introducing methylpiperazine and extending the conjugated system, SNL can locate lysosomes and exhibit absorption and emission both in the near-infrared (NIR) region. In addition, SNL is sensitive to polarity and can be used for sensitive detection of lysosomal polarity changes. Unexpectedly, SNL targets and images the lungs and liver of mice. Subsequently, hyperglycemia-stimulated cell models and diabetic mouse models were successfully established, and SNL was utilized to reveal that polarity can be used as a diagnostic signal of diabetic complications. Notably, SNL for the first time confirmed the lung injury and liver injury caused by diabetes using the fluorescent probes method, providing a new approach for the diagnosis of diabetes complications.

One Stone, Three Birds: A Smart Single Fluorescent Probe for Simultaneous and Discriminative Imaging of Lysosomes, Lipid Droplets, and Mitochondria.

Complex intracellular life processes are usually completed through the cooperation of multiple organelles. Real-time tracking of the interplays between multiple organelles with a single fluorescent probe (SFP) is very helpful to deepen our understanding of complex biological processes. So far, SFP for simultaneously differentiating and visualizing of more than two different organelles has not been reported. Herein, we report an SFP (named ICM) that can be used for simultaneously differentiating and visualizing three important organelles: mitochondria, lysosomes, and lipid droplets (LDs). The probe can simultaneously light up mitochondria/lysosomes (∼700 nm) and LDs (∼480 nm) at significantly different emission wavelengths with high fidelity, and mitochondria and lysosomes can be effectively distinguished by their different shapes and fluorescence intensities. With this smart probe, real-time and simultaneous tracking of the interplays of these three organelles was successfully achieved for the first time.

Kidney-Targeted Near-Infrared Fluorescence Probe Reveals That SO2 Is a Biomarker for Cisplatin-Induced Acute Kidney Injury.

With the widespread use of drugs, drug-induced acute kidney injury (AKI) has become an increasingly serious health concern worldwide. Currently, early diagnosis of drug-induced AKI remains challenging because of the lack of effective biomarkers and noninvasive imaging tools. SO2 plays important physiological roles in living systems and is an important antioxidant for maintaining redox homeostasis. However, the relationship between SO2 (in water as SO32-/HSO3-) and drug-induced AKI remains largely unknown. Herein, we report the highly sensitive near-infrared fluorescence probe DSMN, which for the first time reveals the relationship between SO2 and drug-induced AKI. The probe responds to SO32-/HSO3- selectively and rapidly (within seconds) and shows a significant turn-on fluorescence at 710 nm with a large Stokes shift (125 nm). With these properties, the probe was successfully applied to detect SO2 in living cells and mice. Importantly, the probe can selectively target the kidneys, allowing for the detection of changes in the SO2 concentration in the kidneys. Based on this, DSMN was successfully used to detect cisplatin-induced AKI and revealed an increase in the SO2 levels. The results indicate that SO2 is a new biomarker for AKI and that DSMN is a powerful tool for studying and diagnosing drug-induced AKI.

Selective Visualization of Tumor Cell Membranes and Tumors with a Viscosity-Sensitive Plasma Membrane Probe.

Cancer is a worldwide health problem. Revealing the changes in the microenvironment after cell carcinogenesis is helpful to understand cancer and develop sensitive methods for cancer diagnosis. We developed herein a viscosity-responsive plasma membrane probe (TPA-S) that was successfully used to probe the viscosity difference between normal and tumor cell plasma membranes for the first time. The probe shows AIE properties with good water solubility, significant near-infrared (NIR) fluorescence responses to viscosity with high sensitivity, and excellent cell membrane location performance. With these features, our experiments showed that TPA-S could selectively visualize cancer cell plasma membranes, revealing that the plasma membrane of tumor cells is more viscous than that of normal cells. In addition, TPA-S was successfully applied to specifically light up tumors. Altogether, this work explored the changes of cell membrane viscosity after canceration, provided a new method for selective visualization of tumor cells, and opened up a new approach for cancer diagnosis.

Two Water-Soluble and Wash-Free Fluorogenic Probes for Specific Lighting Up Cancer Cell Membranes and Tumors.

The construction of microenvironment-sensitive probes with good cell membrane-targetability can reveal the fundamental properties of cell membranes. Herein, two polarity-sensitive probes, termed MEMs were reported for the first time to specifically light up cancer cell membranes. Both probes were designed with tetrahydroquinoxaline coumarin amide as the fluorophore, and quaternary ammonium groups were appended to increase water solubility and target cell membranes. In vitro studies showed that the fluorescence of both probes displayed strong polarity dependence and had a wide linear range to polarity (Δf). MEMs also displayed excellent cell membrane targeting ability and could long-term light up cell membranes with red fluorescence and a wash-free process. More excitingly, MEMs could specifically light up cancer cell membranes, revealing that cancer cells might have lower cell membrane polarity than normal cells. In vivo studies showed that MEMs could also effectively distinguish tumors from normal tissues. Overall, this work has not only developed two polarity-sensitive probes with good cell membrane targetability, but also provided new insights and methods for an in-depth understanding of cancer cells and cancer diagnosis.

Polarity-Sensitive Cell Membrane Probe Reveals Lower Polarity of Tumor Cell Membrane and Its Application for Tumor Diagnosis.

Cancer is a health threat worldwide, and it is urgent to develop more sensitive cancer detection methods. Herein, a polarity-sensitive cell membrane probe (named COP) was developed for detecting cancer cells and tumors sensitively and selectively at the cell membrane level. The probe shows a strong polarity-dependent fluorescence and excellent cell membrane targeting ability to visualize cell membrane with red fluorescence with a non-washing process. Notably, COP can selectively light up the tumor cell membranes, which reveals that cancer cell membranes have lower polarity than normal cell membranes. The giant unilamellar vesicle model and cell imaging studies proved this. Moreover, COP can effectively and selectively light up tumors. Overall, this work demonstrates that the polarity of the tumor cell membrane is quite different to normal cell membranes, and based on this, sensitive membrane probes can be developed to selectively visualize cancer cells and tumors, which opens up a new way for tumor diagnosis at the cellular level.

[Clinical characteristics and genetic analysis of a Chinese pedigree affected by glycogen storage disease type Ia with gout as the first manifestation].

OBJECTIVE: To explore the clinical and genetic characteristics of a Chinese pedigree affected by glycogen storage disease (GSD) type Ia with gout as the first manifestation. METHODS: Clinical and biochemical data of the pedigree were collected. Available members of the pedigree were subjected to gene sequencing, and the result was analyzed by bioinformatics software. The pedigree was followed up for five years. RESULTS: The proband was a young female manifesting recurrent gout flare, hypoglycemia, and hypertriglyceridemia. One of her younger brothers also presented with dysplasia and hepatic adenoma. Gene sequencing revealed that the proband and her younger brother both harbored c.1022T>A (p.I1e341Asn) and c.230+5G>A compound heterozygous variants of the G6PC gene , which were inherited from their father and mother, respectively. Among these, the c.230+5G>A is an intron region variant which was unreported previously, and bioinformatics analysis showed that it may impact mRNA splicing of the gene. The proband was treated with raw corn starch, allopurinol, and fenofibrate. Gout was well controlled, and she had given birth to a baby girl without GSD. CONCLUSION: GSD Ia should be considered among young gout patients with hypoglycemia and hepatomegaly, for which gene sequencing is warranted. GSD Ia has a good prognosis after comprehensive treatment with diet and medicine.

Real-Time and High-Fidelity Tracking of Lysosomal Dynamics with a Dicyanoisophorone-Based Fluorescent Probe.

The development of high-performance probes that can visualize and track the dynamic changes of lysosomes is very important for the in-depth study of lysosomes. Herein, we report that a dicyanoisophorone-based probe (named DCIP) can be used for high-fidelity imaging of lysosomes and lysosomal dynamics. DCIP can be easily prepared and shows strong far-red to near-infrared emissions centered at 653 nm in water with a huge Stokes shift (224 nm), high quantum yield (Φ = 0.15), high pKa value (∼8.79), and good biocompatibility. DCIP also shows good cell permeability and can label lysosomes rapidly with bright fluorescence without a time-consuming washing process before imaging. DCIP also possesses good photostability and negligible background, making it effective for long-term and high spatiotemporal resolution (0.44 s of exposure) imaging of lysosomes. Moreover, DCIP achieved high-fidelity tracking of lysosomal dynamics at an extremely low concentration (1 nM). Finally, we also demonstrated that DCIP could real-time track the interactions of lysosomes with other organelles (damaged mitochondria as a model) and image the drug-escape processes from lysosomes. All of the results show that DCIP holds broad prospects in lysosome-related research.

STAT1 facilitates oestrogen receptor α transcription and stimulates breast cancer cell proliferation.

Oestrogen receptor α (ERα) is overexpressed in two-thirds of all breast cancer cases and is involved in breast cancer development and progression. Although ERα -positive breast cancer can be effectively treated by endocrine therapy, endocrine resistance is an urgent clinical problem. Thus, further understanding of the underlying mechanisms involved in ERα signalling is critical in dealing with endocrine resistance in patients with breast cancer. In the present study, unbiased RNA sequence analysis was conducted between the MCF-7 and MCF-7 tamoxifen-resistant (LCC2) cell lines in order to identify differentially expressed genes. The whole transcriptomic data indicated that the JAK-STAT pathway is markedly up-regulated, particularly the ISGF3 complex. As the critical effectors, STAT1 and IRF9 were up-regulated 5- and 20-fold, respectively, in LCC2 cells. The biological experiments indicated that STAT1 is important for ERα signalling. Depletion of STAT1 or inhibition of STAT1 function significantly decreased levels of ERα protein, ERα -target gene expression and cell proliferation in both the MCF-7 and LCC2 cell lines. Chromatin immunoprecipitation revealed that ERα transcription is associated with STAT1 recruitment to the ERα promoter region, suggesting that transcriptional regulation is one mechanism by which STAT1 regulates ERα mRNA levels and ERα signalling in breast cancer cells. The present study reveals a possible endocrine-resistant mechanism by which STAT1 modulates ERα signalling and confers tamoxifen resistance. Targeting of STAT1 is a potential treatment strategy for endocrine-resistant breast cancers.

Performance and microbial community of the completely autotrophic nitrogen removal over nitrite process with a submerged aerated biological filter.

Stable performance is a technical problem in the completely autotrophic nitrogen removal over nitrite (CANON) process with one single stage, which needs to be addressed. In the current work, a laboratory-scale submerged aerated biological filter (SABF) with a 3-L working volume was introduced into the CANON process to enhance its stable performance for 290 days under the following conditions: temperature of 30 ± 1 °C and dissolved oxygen (DO) level of 0.2-0.8 mg·L-1. The results showed that the average ammonium nitrogen removal efficiencies (ANRE) and total nitrogen removal efficiencies (TNRE) were 97.4% and 75.7%, respectively. A 16S rRNA gene high-throughput sequencing technology confirmed the phyla Proteobacteria and Planctomycetes as the ammonium oxidizing bacteria (AOB) and anaerobic ammonia-oxidizing bacteria (AnAOB) of this CANON process with SABF, respectively. The major contributor to nitrogen removal was the genus Candidatus Brocadia, in Brocadiae. The aim is to present an effective strategy as a reference for the design of full-scale plant for the CANON process.

Small extracellular vesicles-shuttled miR-23a-3p from mesenchymal stem cells alleviate renal fibrosis and inflammation by inhibiting KLF3/STAT3 axis in diabetic kidney disease.

Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (MSC-sEV) provide a pragmatic solution as a cell-free therapy for patients with diabetic kidney disease (DKD). However, the underlying protective mechanisms of MSC-sEV remain largely unknown in DKD. Invivo and in vitro analyses demonstrated that MSC-sEV attenuated renal fibrosis and inflammation of DKD. The underlying mechanism of the MSC-sEV-induced therapeutic effect was explored by high-throughput sequencing, which identified the unique enrichment of a set of miRNAs in MSC-sEV compared with human skin fibroblasts-sEV (HSF-sEV). Vitro experiments demonstrated that the protective potential was primarily attributed to miR-23a-3p, one of the most abundant miRNAs in MSC-sEV. Further, overexpression or knockdown analyses revealed that miR-23a-3p, and its target Krüppel-like factor 3 (KLF3) suppressed the STAT3 signaling pathway in high glucose (HG) induced HK-2 cells were essential for the renal-protective property of MSC-sEV. Moreover, we found that miR-23a-3p was packaged into MSC-sEV by RNA Binding Motif Protein X-Linked (RBMX) and transmitted to HG-induced HK-2 cells. Finally, inhibiting miR-23a-3p could mitigate the protective effects of MSC-sEV in db/db mice. These findings suggest that a systemic administration of sEV derived from MSC, have the capacity to incorporate into kidney where they can exert renal-protective potential against HG-induced injury through delivery of miR-23a-3p.

Rheumatoid arthritis with pulmonary accelerated rheumatoid nodules treated by baricitinib: a case-based review.

Pulmonary accelerated rheumatoid nodules (ARN) represent a rare occurrence within the context of rheumatoid arthritis (RA), with conventional treatment typically involving corticosteroids. In this report, we present a unique case of pulmonary ARN managed with baricitinib, a Janus kinase inhibitor. The patient, a 46-year-old woman diagnosed with RA, initially displayed no evident pulmonary nodules upon pulmonary imaging. Her treatment regimen encompassed corticosteroids, methotrexate, and leflunomide. Nevertheless, a chest computed tomography (CT) scan conducted after a year unveiled the presence of multiple bilateral pulmonary nodules. A thoracoscopic biopsy of these nodules confirmed the presence of rheumatoid nodules. Treatment with baricitinib, a Janus kinase inhibitor or synthetic disease-modifying antirheumatic drug (DMARD), effectively reduced the size of the nodules. Our review of 45 articles on ARN published since 1986 found that nine of them reported 13 cases of pulmonary ARN. These nodules may be caused by certain synthetic and biological DMARDs and often present with respiratory symptoms. CT scans typically reveal multiple solid nodules or ground-glass opacities, some of which may have cavities. Treatment customarily involves discontinuing the suspected drugs and administering corticosteroids. This case suggests that Janus kinase inhibitors may be an effective treatment option for ARN.

Dependence of evolution of Cyanobacteria superiority on temperature and nutrient use efficiency in a meso-eutrophic plateau lake.

Algal blooms in lakes have been a challenging environmental issue globally under the dual influence of human activity and climate change. Considerable progress has been made in the study of phytoplankton dynamics in lakes; The long-term in situ evolution of dominant bloom-forming cyanobacteria in meso-eutrophic plateau lakes, however, lacks systematic research. Here, the monthly parameters from 12 sampling sites during the period of 1997-2022 were utilized to investigate the underlying mechanisms driving the superiority of bloom-forming cyanobacteria in Erhai, a representative meso-eutrophic plateau lake. The findings indicate that global warming will intensify the risk of cynaobacteria blooms, prolong Microcystis blooms in autumn to winter or even into the following year, and increase the superiority of filamentous Planktothrix and Cylindrospermum in summer and autumn. High RUETN (1.52 Biomass/TN, 0.95-3.04 times higher than other species) under N limitation (TN < 0.5 mg/L, TN/TP < 22.6) in the meso-eutrophic Lake Erhai facilitates the superiority of Dolichospermum. High RUETP (43.8 Biomass/TP, 2.1-10.2 times higher than others) in TP of 0.03-0.05 mg/L promotes the superiority of Planktothrix and Cylindrospermum. We provided a novel insight into the formation of Planktothrix and Cylindrospermum superiority in meso-eutrophic plateau lake with low TP (0.005-0.07 mg/L), which is mainly influenced by warming, high RUETP and their vertical migration characteristics. Therefore, we posit that although the obvious improvement of lake water quality is not directly proportional to the control efficacy of cyanobacterial blooms, the evolutionary shift in cyanobacteria population structure from Microcystis, which thrives under high nitrogen and phosphorus conditions, to filamentous cyanobacteria adapted to low nitrogen and phosphorus levels may serve as a significant indicator of water quality amelioration. Therefore, we suggest that the risk of filamentous cyanobacteria blooms in the meso-eutrophic plateau lake should be given attention, particularly in light of improving water quality and global warming, to ensure drinking water safety.

Association of serum concentrations of remnant cholesterol with incident cardiovascular disease in patients with rheumatoid arthritis: A real-world data from 2001 to 2022.

BACKGROUND: Remnant cholesterol (RC) promotes cardiovascular disease (CVD) in the general population, but its role among rheumatoid arthritis (RA) patients remains unknown. We aimed to investigate circulating RC levels associated with incident CVD among Chinese patients with RA. METHODS: A total of 1018 RA patients free of baseline CVD were included and followed up in a prospective RA CVD cohort from 2001 to 2022. Fasting serum levels of triglycerides, total cholesterol (TC), low-density (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured, while RC and Non-HDL-C levels were calculated. The primary exposure was RC levels. A LASSO Cox model was used to select covariates. The Fine-Gray competing risk model was used to estimate hazard ratios (HRs). RESULTS: RA patients had a mean age of 53.9 years, and 802 (78.8%) were females. After a median follow-up of 5.54 years, 131 patients developed CVD with an incidence rate of 21.6 per 1000 person-years. Continuous and quartile-categorized RC levels were associated with incident CVD before and after multivariate adjustment and Bonferroni correction (all P < 0.001). There were no robust associations of other lipids with incident CVD. The fully adjusted HRs for RC were 2.30 (95% CI 1.58-3.35) per 1 mmol/L increase, and 2.40 (1.36-4.25) and 2.81 (1.60-4.94) for patients in the 3rd and 4th versus the 1st quartile, respectively. CONCLUSIONS: Circulating RC levels are positively associated with incident CVD among Chinese RA patients independent of known risk factors, implying its clinically preferable use for improving the stratification of CVD risk in RA patients.

Cell membrane targetable NIR fluorescent polarity probe for selective visualization of cancer cells and early tumor.

The development of a sensitive method for early cancer diagnosis is very important because the early diagnosis of cancer is crucial in preventing the spread of cancer cells and improving patient survival rates. Recent studies showed that cancer cell membranes have lower polarity than normal cell membranes, which provides a new approach for cancer diagnosis at the cell membrane level. We developed herein a highly sensitive cell membrane polarity probe (Cal-M) for early diagnosis of cancer. This probe has low cytotoxicity, good photostability, near-infrared (NIR) fluorescence emission (>700 nm), large Stokes shift, high sensitivity for polarity, excellent cell membrane localization performance, and the ability to selectively light up cancer cells. Using this probe staining, the fluorescence of cancer cells is ∼63 times higher than that of normal cells, demonstrating excellent sensitivity and selectivity of Cal-M. This probe was also successfully used to detect polarity changes on cancer cell membranes and selectively visualize tumors in mice. Notably, the tumor could be visualized sensitively with a size as small as 1.37 mm3, indicating that Cal-M is promising for early diagnosis of tumors.

A new perspective on Alzheimer's disease: m6A modification.

As a neurodegenerative disease, Alzheimer's disease (AD) is characterized by synaptic loss, extracellular plaques of amyloid accumulation, hyperphosphorylation of tau, and neuroinflammation. Various biological processes are affected by epitranscriptomic modifications, which regulate the metabolism of mRNA in cells and regulate the expression of genes. In response to changes in m6A modification levels, the nervous system becomes dysfunctional and plays a significant role in the development of Alzheimer's disease. As a result of recent research, this paper reviews advances in the understanding of the regulatory mechanisms of m6A modification in the occurrence and development of AD. In addition, the article discusses recent research techniques related to animal models of m6A and AD. Furthermore, it discusses the possibility of studying the pathogenesis of AD at the level of the epitranscriptome, identifying early diagnostic markers, and screening for effective treatment options.

Elevated serum cholesterol levels are associated with proteinuria over 0.5 g/day in premenopausal women with systemic lupus erythematosus.

Background: Systemic lupus erythematosus (SLE) commonly occurs in premenopausal women and is associated with elevated estrogen levels. Patients with SLE may have abnormal serum triglyceride (TG) levels, and lipid reportedly promotes kidney damage in patients with nephrosis. Since estrogen regulates lipid levels, we investigated the serum lipid levels of premenopausal women with SLE and their relationship with proteinuria. Methods: This cross-sectional study included 123 premenopausal women with SLE (SLE group), who were classified into 24-h urine protein exceeding 0.5 g (24 h-UPRO > 0.5 g, n = 22) and 24 h-UPRO ≤ 0.5 g (n = 101) subgroups, and 100 similarly aged healthy women (control group). Clinical characteristics and biomarker levels were compared between these groups. The associated factors of proteinuria over 0.5 g/day were evaluated using multivariate logistic regression. A receiver operating characteristic (ROC) curve was plotted to assess the cholesterol (CH) cut-off associated with increased development of proteinuria over 0.5 g/day. Results: The SLE group had significantly higher serum TG levels than that of control group. 24 h-UPRO were significantly correlated with serum creatinine, CH, TG, and uric acid levels. Serum CH level was the greatest associated factor for proteinuria over 0.5 g/day. The area under the ROC curve was 0.843, with a CH cut-off of 4.58 mmol/L. Patients with serum CH above 4.58 mmol/L had a higher proportion of type IV LN, but with no statistical difference. Conclusions: In premenopausal SLE patients, serum TG levels were higher than in healthy women, and serum CH levels were the primary associated factor for proteinuria over 0.5 g/day. Proteinura over 0.5 g/day may occur in women with SLE with serum CH levels >4.58 mmol/L. CH levels may be useful for predicting proteinuria.

Prevalence and influence of hypouricemia on cardiovascular diseases in patients with rheumatoid arthritis.

BACKGROUND: Serum uric acid (SUA) acts as an antioxidant and abnormally low SUA may raise the risk of developing atherosclerotic disorders. There is a U-shaped association between SUA with cardiovascular diseases (CVDs) in general population. However, the prevalence of hypouricemia and its influence on CVDs in rheumatoid arthritis (RA) remains unclear. METHODS: This cross-sectional study collected clinical data from a Chinese RA cohort. Hypouricemia was defined as SUA ≤ 3.0 mg/dL, and hyperuricemia was defined as SUA ≥ 7.0 mg/dL. CVDs were defined as a history of angina pectoris, myocardial infarction, heart failure, stroke and peripheral arterial disease. Restricted cubic spline regression and logistic regression analysis were conducted to evaluate the associations between SUA levels and CVDs. RESULTS: Among 1130 RA patients recruited, the mean age was 53.2 years and 79.0% were female. The prevalence of hypouricemia and hyperuricemia were 10.6% and 12.0%, respectively. RA patients with hyperuricemia had a higher rate of CVDs than normouricemic patients (27.9% vs. 7.1%, P < 0.05). Surprisingly, RA patients with hypouricemia also had a higher rate of CVDs (20.7% vs. 7.1%, P < 0.05) even without higher traditional cardiovascular risk factors. A U-shaped association between SUA levels and total CVDs was found (Pnon-linear < 0.001). Multivariate logistic regression analysis revealed that compared with normouricemia, both hypouricemia [adjusted OR (AOR) = 4.707, 95% CI 2.570-8.620] and hyperuricemia (AOR = 3.707, 95% CI 2.174-6.321) were associated with higher risk of CVDs. CONCLUSIONS: Hypouricemia may be a potential risk factor of CVDs in RA patients.