A dual-channel fluorescent probe targeting lysosomes for differential detection of Cys/Hcy and GSH: Applications in food, pharmaceutical analysis and bioimaging.

Thiols function as antioxidants in food, prolonging shelf life and enhancing flavor. Moreover, thiols are vital biomolecules involved in enzyme activity, cellular signal transduction, and protein folding among critical biological processes. In this paper, the fluorescent probe PYL-NBD was designed and synthesized, which utilized the fluorescent molecule pyrazoline, the lysosome-targeted morpholine moiety, and the sensing moiety NBD. Probe PYL-NBD was tailored for the recognition of biothiols through single-wavelength excitation, yielding distinct fluorescence emission signals: blue for Cys, Hcy, and GSH; green for Cys, Hcy. Probe PYL-NBD exhibited rapid reaction kinetics (<10 min), distinct fluorescence response signals, and low detection limits (15.7 nM for Cys, 14.4 nM for Hcy, and 12.6 nM for GSH). Probe PYL-NBD enabled quantitative determination of Cys content in food samples and L-cysteine capsules. Furthermore, probe PYL-NBD had been successfully applied for confocal imaging with dual-channel detection of biothiols in various biological specimens, including HeLa cells, zebrafish, tumor sections, and Arabidopsis thaliana.

Periconceptional folic acid supplementation and the risks of small and large for gestational age at birth: the mediation effect of maternal homocysteine level during pregnancy.

BACKGROUND: Periconceptional folic acid supplementation (FAS) is widely recommended. However, the role of periconceptional FAS on neonatal birth weight remains unclear. OBJECTIVE: This study aimed to explore the independent effects of periconceptional FAS on the risks of small for gestational age (SGA) and large for gestational age (LGA), and to test the potential mediation role of maternal homocysteine (Hcy) during pregnancy on the above significant associations. METHODS: A large-scale prospective birth cohort was conducted in the Tongzhou Maternal and Child Health Hospital, Beijing, China from June 2018 to August 2019. Periconceptional FAS was evaluated by a self-administered questionnaire on the day of recruitment in early pregnancy (<14th week of gestation). FAS was defined as participants who had taken folic acid (FA) supplements, FA-containing multivitamins, or other FA-containing nutritional supplements. Neonatal birth weight was measured at delivery. Maternal serum Hcy concentrations were measured in early and late pregnancy respectively. Logistic regression analyses were performed to assess the associations between FAS during preconception and/or early pregnancy and the occurrence of SGA or LGA. A mediation model was constructed to determine the role of maternal Hcy concentration on the above associations. RESULTS: FAS before pregnancy (risk ratios [RR]=0.819, 95% confidence interval [CI]: 0.672-1.000, P=0.05), during early pregnancy (RR=0.622, 95%CI: 0.451-0.858) and from pre-pregnancy to early pregnancy (RR=0.564, 95%CI: 0.371-0.857) were associated with a lower risk of LGA. However, no significant association was found between periconceptional FAS and SGA birth. Maternal Hcy concentration in late pregnancy mediated the independent effects of maternal FAS during preconception and early pregnancy on the risks of LGA birth. CONCLUSIONS: Periconceptional FAS was associated with a lower risk of LGA, which may be mediated by the reduced serum Hcy concentration in late pregnancy. The current recommendation of periconceptional FAS should be complied with to reduce the risks of LGA.

Design and synthesis of novel mitochondria-targeted ergosterol peroxide derivatives as potential anti-cancer agents.

Ergosterol peroxide (EP) is a natural steroid compound that has been reported to have significant antitumor activity. However, its poor water solubility and cellular uptake mean that it has weak efficacy against tumor cells. Herein, we designed and synthesized a series of EP derivatives with mitochondrial targeting properties. Of these, compound 15a showed an IC50 value of 0.32 µM against MCF-7 cells, which was 67-fold higher than that of the parental EP (IC50 = 21.46 µM), and was better than cisplatin (IC50 = 4.23 µM), had a selectivity index of 25.28 (IC50MCF-10A/IC50MCF-7). Additionally, compound 15a promoted an increase in intracellular reactive oxygen species levels and a decrease in mitochondrial membrane potential, and blocked the cell cycle in the G0/G1 phase. In a mouse model of breast cancer, 15a showed 89.85 % tumor inhibition at a dose of 20 mg/kg, which is similar to the therapeutic effect of the cisplatin. On the basis of these results, 15a could be considered for further preclinical evaluation for cancer therapy.

[Study on the protective effect of acupuncture on poor ovarian response in mice]. / é’ˆåˆºå¯¹åµå·¢ä½Žååº”å°é¼ åµå·¢çš„ä¿æŠ¤æœºåˆ¶.

OBJECTIVES: To observe the protective effect of acupuncture on ovarian function and its impact on key molecules (Yes associated protein ï¼»YAPï¼½ and transcriptional coactivator with PDZ binding motif ï¼»TAZï¼½) in the Hippo signaling pathway in poor ovarian response (POR) mice, in order to explore its mechanisms underlying improvement of POR by inhibiting ovarian cell apoptosis. METHODS: The mice with regular motility cycle after screening were randomly divided into normal control, model and acupuncture groups, with 12 mice in each group. The POR model was established by gavage of tripterygium wilfordii polyglycoside suspension (50 mg · kg-1·d-1) for 2 weeks, and the mice of the normal control group was received an equal volume of 0.9% sodium chloride solution by gavage. The mice in the acupuncture group received manual acupuncture stimulation of bilateral "Taichong" (LR3) and "Sanyinjiao" (SP6), and "Zhongji" (CV3) and "Guanyuan" (CV4), with the filiform needles retained for 20 min, once daily for successive 10 days. The estrous cycle was determined by using vaginal exfoliated cell smear, and the body mass was detected weekly. The levels of serum anti Mullerian hormone (AMH), follicle stimulating hormone (FSH), estradiol (E2) and luteinizing hormone (LH) were measured using enzyme-linked immunosorbent assay (ELISA). Histopathological changes of the ovarian tissue were observed after H.E. staining, and the apoptosis of ovarian granulosa cells was measured using terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay. The expression levels of YAP, TAZ, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), cysteine aspartic acid specific protease-3 (Caspase-3) mRNAs and proteins were detected using real-time PCR and Western blot, respectively. RESULTS: Compared with the normal control group, the model group had an increase in the rate of estrous cycle disorder, estrous cycle, serum FSH and LH content, and apoptosis of ovarian granulosa cells, and expression levels of Bax and Caspase-3 mRNAs and p-YAP, Bax and Caspase-3 proteins (P<0.01), and a decrease in the body mass, number of retrieved oocytes, ovarian wet weight and ovarian index, serum AMH and E2 contents, and the expression levels of YAP, TAZ, Bcl-2 mRNAs and proteins (P<0.01). After acupuncture intervention, modeling induced increase and decrease of indexes mentioned above were completely reversed (P<0.05, P<0.01). H.E. staining showed deformed ovarian structure, reduced number of normal developing follicles and increased number of atretic follicles, disordered arrangement of the granulosa cells with fewer hierarchy in the model group, which was improved in the acupuncture group, such as increase in the number and improvement in the shape of normal ovarian follicles and reduction of the atretic follicles. CONCLUSIONS: Acupuncture intervention can inhibit the apoptosis of ovarian granulosa cells and improve the ovarian function of POR mice, which may be related to its effects in up-regulating the expressions of YAP, TAZ (key molecules of Hippo signaling pathway).

Identification and validation of novel genes related to immune microenvironment in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most complicated chronic inflammatory diseases in women of reproductive age and is one of the primary factors responsible for infertility. There is substantial dispute relating to the pathophysiology of PCOS. Consequently, there is a critical need for further research to identify the factors underlying the pathophysiology of PCOS. Three transcriptome profiles of granulosa cells from patients with PCOS and normal controls were obtained from the gene expression integration database. We also obtained relevant microarrays of granulocytes prepared from PCOS patients and normal controls from the gene expression integration database. Then, we used the R package to perform correlations and identify differences between PCOS and normal controls with regard to immune infiltrating cells and functionality. Subsequently, intersecting genes were identified and risk models were constructed. Finally, the results were validated by enzyme linked immunosorbent assay and real-time PCR. We identified 8 genes related to cuproptosis (SLC31A1, PDHB, PDHA1, DLST, DLD, DLAT, DBT, and ATP7A) and 5 genes related to m7G (SNUPN, NUDT16, GEMIN5, DCPS, and EIF4E3) that were associated with immune infiltration. Furthermore, the expression levels of DLAT (P = .049) and NUDT16 (P = .024) differed significantly between the PCOS patients and normal controls, as revealed by multifactorial analysis. Both DLAT and NUDT16 were negatively correlated with immune cell expression and function and expression levels were significantly lower in the PCOS group. Finally, real-time PCR and enzyme linked immunosorbent assay demonstrated that the expression levels of DLAT and NUDT16 were significantly reduced in the granulosa cells of PCOS patients. In conclusion, our findings shed fresh light on the roles of immune infiltration, cuproptosis, and m7G alternations in PCOS. We also provide a reliable biomarker for the pathological classification of PCOS patients.

Design, synthesis and antitumor effects of lupeol quaternary phosphonium salt derivatives.

Lupeol is a natural pentacyclic triterpenoid with a wide range of biological activities. To improve the water solubility and targeting of lupeol, in the following study, we synthesized 27 lupeol derivatives in the first series by introducing lipophilic cations with lupeol as the lead compound. Through the screening of different cancer cells, we found that some of the derivatives showed better activity than cisplatin against human non-small cell lung cancer A549 cells, among which compound 6c was found to have an IC50 value of 1.83 µM and a selectivity index of 21.02 (IC50MRC-5/IC50A549) against A549 cells. To further improve the antiproliferative activity of the compounds, we replaced the ester linkage of the linker with a carbamate linkage and synthesized a second series of five lupeol derivatives which were screened for activity, among which compound 14f was found to have an IC50 value of 1.36 µM and a selectivity index of 15.60 (IC50MRC-5/IC50A549) against A549 cells. We further evaluated the bioactivity of compounds 6c and 14f and found that both compounds induced apoptosis in A549 cells, promoted an increase in intracellular reactive oxygen species and decrease in mitochondrial membrane potential, and inhibited the cell cycle in the S phase. Of the compounds, compound 14f showed stronger bioactivity than compound 6c. We then selected compound 14f for molecular-level Western blot evaluation and in vivo evaluation in the zebrafish xenograft A549 tumor cell model. Compound 14f was found to significantly downregulate Bcl-2 protein expression and upregulate Bax, Cyt C, cleaved caspase-9, and cleaved caspase-3 protein expression, and 14f was found to be able to inhibit the proliferation of A549 cells in the zebrafish xenograft model. The above results suggest that compound 14f has great potential in the development of antitumor drugs targeting mitochondria.

The current state of MRI-based radiomics in pituitary adenoma: promising but challenging.

In the clinical diagnosis and treatment of pituitary adenomas, MRI plays a crucial role. However, traditional manual interpretations are plagued by inter-observer variability and limitations in recognizing details. Radiomics, based on MRI, facilitates quantitative analysis by extracting high-throughput data from images. This approach elucidates correlations between imaging features and pituitary tumor characteristics, thereby establishing imaging biomarkers. Recent studies have demonstrated the extensive application of radiomics in differential diagnosis, subtype identification, consistency evaluation, invasiveness assessment, and treatment response in pituitary adenomas. This review succinctly presents the general workflow of radiomics, reviews pertinent literature with a summary table, and provides a comparative analysis with traditional methods. We further elucidate the connections between radiological features and biological findings in the field of pituitary adenoma. While promising, the clinical application of radiomics still has a considerable distance to traverse, considering the issues with reproducibility of imaging features and the significant heterogeneity in pituitary adenoma patients.

[Exploration of JI Laixi's academic thought of acupuncture and moxibustion in clinical practice].

The paper summarizes Professor JI Laixi's academic thought on acupuncture and moxibustion. Professor JI Laixi inherits and carries forward the theory and technical system of Shanxi "new nine needles", deepens its academic connotation, and promotes clinical practice. He advocates the integration of Chinese and western medicine, and the inclusion of multiple disciplines, e.g. acupuncture and moxibustion of Chinese medicine and modern anatomy. He takes the lead in proposing a new approach to the treatment of meridian diseases of limbs, "treating the neck region for the diseases of head, treating the abdominal region for the diseases of the lumbar region, and treating the lumbar region for the disease of knees". He proposes the acupoint prescription being standardized and simplified, explores the system of acupoint prescription and establishes the prescriptions for gastric diseases, intestinal diseases and antihypertension.

Moxibustion with seed-size moxa cones alleviates colonic injury in mice with ulcerative colitis by regulating TLR4/MyD88/NF-κB signaling pathway. / 麦粒灸调控TLR4/MyD88/NF-κBä¿¡å·é€šè·¯å‡è½»æºƒç–¡æ€§ç»“è‚ ç‚Žå°é¼ ç»“è‚ æŸä¼¤çš„æœºåˆ¶ç ”ç©¶.

OBJECTIVES: To observe the effect of moxibustion with seed-size moxa cones on the Toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88)/nuclear transcription factor-κB(NF-κB) signaling pathway in mice with ulcerative colitis(UC), so as to explore the therapeutic mechanism of moxibustion with seed-size moxa cones on colonic injury in UC. METHODS: Forty male C57BL/6 mice were randomly divided into blank group, model group, moxibustion group, and western medicine group, with 10 mice in each group. The UC mouse model was established by 3% DSS solution by free drinking for 7 consecutive days. Mice in the moxibustion group were treated with seed-size moxa cones at "Zhongwan"(CV12), "Tianshu"(ST25) and "Shangjuxu"(ST37), 3 moxa cones per point, with each cone applied for approximately 30 s, while mice in the western medicine group were orally administered with 300 mg/kg mesalazine solution, which were both conducted once a day for 7 consecutive days. The general condition of mice was observed every 2 days, and the disease activity index (DAI) score was calculated. HE staining was used to observe the morphology of colonic tissue in mice. ELISA was used to detect the serum interleukin(IL)-1ß, tumor necrosis factor(TNF)-α, IL-6, and IL-8 contents. Immunohistochemistry was used to detect the positive expression of TLR4 and MyD88 in colonic tissue of mice. Real-time fluorescence quantitative PCR was used to detect the expression levels of TLR4, MyD88, and NF-κB p65 mRNAs in colonic tissue. RESULTS: Compared with the blank group, varying degrees of soft or watery stools were observed, colon length and body weight were decreased(P<0.01) in mice of the model group, while DAI score, colon weight index, mucosal damage score, colonic pathological score, serum IL-1ß, TNF-α, IL-6, and IL-8 contents, positive expressions of TLR4 and MyD88, and TLR4, MyD88, and NF-κB p65 mRNA expressions in colonic tissue were increased(P<0.01). Compared with the model group, improved fecal characteristics were observed, colon length and body weight were increased(P<0.01) in mice of the moxibustion group and western medicine group, while DAI scores, colon weight indexes, mucosal damage scores, colonic pathological score, serum contents of IL-1ß, TNF-α, IL-6, and IL-8, positive expressions of TLR4 and MyD88, and TLR4, MyD88, and NF-κB p65 mRNA expressions in colonic tissue were decreased(P<0.01, P<0.05). There was no significant difference in the above indicators between the moxibustion group and the western medicine group. CONCLUSIONS: Moxibustion with seed-size moxa cones may alleviate colonic injury in UC mice by regulating the TLR4/MyD88/NF-κB signaling pathway and reducing the release of inflammatory factors.

CAFs-derived Exosomal miR-889-3p Might Repress M1 Macrophage Polarization to Boost ESCC Development by Regulating STAT1.

Cancer-associated fibroblasts (CAFs) represent one of the major components of the tumor stroma, which might create an immunosuppressive tumor microenvironment by inducing and functionally polarizing protumoral macrophages. Previous studies indicated that exosomes derived from CAFs might transmit regulating signals and boost esophageal squamous cell carcinoma (ESCC) development. This study is designed to explore the role and mechanism of CAFs-derived exosomal microRNA-889-3p (miR-889-3p) in ESCC progression. Macrophage polarization was detected using flow cytometry. miR-889-3p, Tumor necrosis factor alpha (TNF-α), and inducible nitric oxide synthase (iNOS) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, cycle progression, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), scratch assay, and Transwell assays. α-SMA, FAP, CD63, CD81, and signal transducer and activator of transcription 1 (STAT1) protein levels were detected using western blot. Exosomes were characterized using an electron microscope and nanoparticle tracking analysis (NTA). Binding between miR-889-3p and STAT1 was predicted by Starbase, and verified by a dual-luciferase reporter and RNA pull-down. The effect of CAFs-derived exosomal miR-889-3p on ESCC tumor growth in vivo was detected using mice xenograft assay. miR-889-3p level was decreased in LPS-induced M0 macrophages. CAF-derived exosomal miR-889-3p knockdown suppressed ESCC proliferation, migration, and invasion. CAFs might transfer miR-889-3p to M0 macrophages via exosomes. STAT1 was a target of miR-889-3p. Besides, in vivo studies confirmed that CAFs-derived exosomal miR-889-3p can accelerate ESCC tumor growth by regulating STAT1. CAFs-derived exosomal miR-889-3p facilitates esophageal squamous cell carcinoma cell proliferation, migration, and invasion by inhibiting M1 macrophage polarization through down-regulation of STAT1, providing a promising therapeutic target for ESCC.

Biodegradable Piezoelectric-Conductive Integrated Hydrogel Scaffold for Repair of Osteochondral Defects.

Osteochondral injury is a prevalent condition for which no specific treatment is currently available. This study presents a piezoelectric-conductive scaffold composed of a piezoelectric cartilage-decellularized extracellular matrix (dECM) and piezoelectric-conductive modified gelatin (Gel-PC). The piezoelectricity of the scaffold is achieved through the modification of diphenylalanine (FF) assembly on the pore surface, while the conductive properties of scaffold are achieved by the incorporating poly(3,4-ethylenedioxythiophene). In vitro experiments demonstrate that bone marrow mesenchymal stem cells (BMSCs) undergo biphasic division during differentiation. In vivo studies using a Parma pig model of osteochondral defects demonstrate that the piezoelectric-conductive scaffold exhibits superior reparative efficacy. Notably, the generation of electrical stimulation is linked to joint movement. During joint activity, mechanical forces compress the scaffold, leading to deformation and the subsequent generation of an electric potential difference. The positive charges accumulated on the upper layer of the scaffold attract BMSCs, promoting their migration to the upper layer and chondrogenic differentiation. Meanwhile, the negative charges in the lower layer induce the osteogenic differentiation of BMSCs. Overall, this piezoelectric-conducive scaffold provides a promising platform for the effective repair of osteochondral defects.

Polydopamine-Cloaked Nanoarchitectonics of Prussian Blue Nanoparticles Promote Functional Recovery in Neonatal and Adult Ischemic Stroke Models.

Ischemic stroke is a devastating disease and one of the leading causes of mortality worldwide. Overproduction of reactive oxygen species and inflammatory response contribute to secondary damage following ischemic insult. Nanozymes with robust anti-oxidative stress properties possess therapeutic possibility for ischemic insult. However, insufficiency of nanozyme accumulation in the neuronal mitochondria hindered their application. Herein, we constructed polydopamine-coated Prussian blue nanoparticles (PB@PDA NPs) to realize the targeting neuronal mitochondria for ischemic stroke, with the properties of antioxidant and anti-inflammation. After administration, much higher accumulation of PB@PDA NPs in the brain was observed compared to that in the PB NP group. Moreover, PB@PDA NPs effectively attenuated brain infarct than that of PB NPs in neonatal mice following hypoxia-ischemia (HI) insult. PB@PDA NPs mainly colocated with neuronal mitochondria in vivo and in vitro. Apart from attenuating oxidative stress, PB@PDA NPs also suppressed neuronal apoptosis and counteracted inflammation, which effectively promote a short- and long-term functional recovery in HI mice. Further, the therapeutic efficacy of PB@PDA NPs was also found in adult ischemic mice via tail vein injection. Collectively, these findings illustrate that PB@PDA NPs via system injection accumulate in neuronal mitochondria and are beneficial for ischemic stroke.

Transcriptome and proteomic analysis reveal the protective mechanism of acupuncture on reproductive function in mice with asthenospermia.

Acupuncture is an integral component of complementary and alternative medicine that has been reported to enhance sperm motility, improve semen quality, and consequently augment male fertility. However, the precise mechanisms of action and the underlying molecular pathways remain unclear. In the present study, we aimed to elucidate the potential mechanisms through which acupuncture improves reproductive function in a mouse model of cyclophosphamide-induced asthenozoospermia. We collected sperm from the epididymis for semen analysis, collected serum to determine gonadotropin and oxidative stress marker levels, conducted histological examination of testicular tissue using hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and observed mitochondrial morphology using transmission electron microscopy (TEM). We also assessed oxidative stress levels and total iron content in testicular tissue and validated the proteomic and transcriptomic analysis results of testicular tissue using real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR), protein imprinting analysis, and immunohistochemistry (IHC). Our results indicate that acupuncture enhances sperm quality in asthenozoospermic mice; increases serum testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels; and attenuates oxidative damage, iron accumulation, and mitochondrial injury in mouse testicular tissues. Through protein and transcriptomic analyses, we identified 21 key genes, of which cytochrome b-245 heavy chain (CYBB), glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 1 (ACSL1), and ferritin mitochondria (FTMT) were closely associated with ferroptosis. RT-qPCR, protein imprinting, and immunofluorescence (IF) analyses collectively indicated that acupuncture reduced ACSL1 and CYBB expression, and increased GPX4 and FTMT expression. Overall, the ferroptosis pathway associated with ACSL1/CYBB/FTMT/GPX4 represents a potential strategy through which acupuncture can improve the reproductive function in asthenozoospermic mice.

Responses of ecosystem service trade-offs and synergies in Guangfo Metropolitan Area to multidimensional expansion of urban space.

Understanding the responses of ecosystem service trade-offs and synergies in metropolitan areas to the multidimensional expansion of urban space is of great significance for the optimization of regional land spatial pattern and high-quality development. With the Guangfo Metropolitan Area as research region, we used land use data and natural ecological environment data from 2000 to 2020 to measure the expansion characteristics of urban space in the dimensions of scale, distribution, and morphology by using the landscape pattern indices. We further calculated four main ecosystem services: urban cooling, habitat quality, recreation, and water conservation by the InVEST model, quantified the trade-off and synergistic relationship of multiple ecosystem services by the coupling coordination degree model, and explored its response to multidimensional urban spatial expansion by using the multi-scale geographically weighted regression model. The results showed that urban land use scale in the Guangfo Metropolitan Area continued to increase from 2000 to 2020, with an accelerated growth rate from 2010 to 2020. The ave-rage patch area of urban land in the central area and the urban land of small patches in the northeast increased, evolving from a "dual-center" structure to a "single-center" one. The distance between urban land patches in the Guangfo Metropolitan Area was relatively small, indicating a compact distribution of urban land. The distance between newly developed urban land patches was also small, but had gradually increased in recent years. The patch shape of urban land was relatively regular and less complex, but the complexity of the newly added urban land gra-dually increased. The ecosystem service trade-offs and synergies in the Guangfo Metropolitan Area had undergone significant changes, with a decrease in synergies and an increase in trade-off, and extreme trade-offs had gradually become dominant. The response of ecosystem services synergies to changes in urban land use scale was the most intense and had spatial heterogeneity, while the response to the change of distribution and morphological characte-ristics of urban land showed periodic differences.

Discovery and Optimization of Ergosterol Peroxide Derivatives as Novel Glutaminase 1 Inhibitors for the Treatment of Triple-Negative Breast Cancer.

In this study, novel ergosterol peroxide (EP) derivatives were synthesized and evaluated to assess their antiproliferative activity against four human cancer cell lines (A549, HepG2, MCF-7, and MDA-MB-231). Compound 3g exhibited the most potent antiproliferative activity, with an IC50 value of 3.20 µM against MDA-MB-231. This value was 5.4-fold higher than that of the parental EP. Bioassay optimization further identified 3g as a novel glutaminase 1 (GLS1) inhibitor (IC50 = 3.77 µM). In MDA-MB-231 cells, 3g reduced the cellular glutamate levels by blocking the glutamine hydrolysis pathway, which triggered reactive oxygen species production and induced caspase-dependent apoptosis. Molecular docking indicated that 3g interacts with the reaction site of the variable binding pocket by forming multiple interactions with GLS1. In a mouse model of breast cancer, 3g showed remarkable therapeutic effects at a dose of 50 mg/kg, with no apparent toxicity. Based on these results, 3g could be further evaluated as a novel GLS1 inhibitor for triple-negative breast cancer (TNBC) therapy.

Impact of growth hormone-secreting pituitary adenoma on limbic system and its correlation with cognitive impairment.

Purpose: To assess the quantitative gray matter volume of the limbic system in growth hormone-secreting pituitary adenoma (GHPAs) patients and its correlation to cognitive function. Method: 91 right-handed patients with pituitary adenomas were retrospectively included from the First Affiliated Hospital of Sun Yat-sen University -48 with GHPAs and 43 with non-functioning pituitary adenomas (NFPAs). Participants underwent serum hormone assessment, regular sellar MRI scanning with T1WI-MPRAGE. Cognitive function was gauged using MoCA and MMSE. Brain region auto-segmentation and gray matter volume calculation were conducted on the Brainsite platform. Results: Compared to NFPAs patients, GHPAs patients had higher gray matter volume (758,285 vs 674,610 mm³, p < 0.001). No significant volumetric differences in both sides of limbic system gray matter while there were evident differences in the relative volumes of limbic system gray matter between groups. GHPAs patients scored lower on MOCA (24.0 (2.18) vs 25.1 (2.28), p < 0.031), with no difference in MMSE. We observed a significant correlation between the relative limbic volume and MOCA scales, while no evident correlation was found between relative limbic volume and serum hormone or tumor aggressiveness. Univariate and multivariate Logistic regression showed that hippocampus and limbic cortex (parahippocampal gyrus and internal olfactory area) of advantageous hemisphere correlated significantly with occurrence of mild cognitive impairment with the C-statistic reaching 0.90. Conclusion: Patients with GHPAs show a relative decrease in limbic gray matter volume, especially in the hippocampus and limbic cortex of the dominant hemisphere, which is associated with mild cognitive impairment.

Al-Doped CuS Colloidal Nanocrystals as a Highly Efficient Electrochemiluminescence Emitter for the Ultrasensitive Detection of Circulating Tumor DNA.

Herein, CuS colloidal nanocrystals (NCs) with adjustable band gap and good film forming ability have been synthesized as new ECL materials. Furthermore, the band gap and oxygen vacancy (OV) content of CuS NCs are regulated by Al3+ doping, which significantly improves the ECL response of CuS NCs. First, the band gap of CuS-Al NCs decreases after doping with Al3+, which makes it easier for electrons to transition across the band gap. At the same time, the oxygen vacancy of CuS-Al NCs increases, which is conducive to improving the conductivity and promoting charge transfer, thus improving the ECL performance of CuS-Al NCs. Circulating tumor DNA (ctDNA) is an important tumor marker, and its sensitive monitoring is of great significance for tumor diagnosis, treatment, and prognosis detection. Therefore, an ECL biosensor for ultrasensitive detection of circulating tumor DNA (ctDNA) was prepared by using CuS-Al NCs as luminescent material and combining multiple antidromic hybrid chain reaction (anti-HCR) strategy mediated by the target. Compared with the process of target-induced HCR generation, this strategy first forms multiple HCR products and then destroys the already formed HCR products by target-induced destruction, which enhances the sensitivity of target response and improves the reaction efficiency. The constructed biosensor has good detection performance, and the detection limit is as low as 2.74 aM. This work puts forward the luminescence phenomenon of colloidal nanocrystals as new ECL materials, which broadens the application of ECL technology in ultrasensitive biochemical detection.

Visual Tracking of Hydrogen Sulfide: Application of a Novel Lysosome-Targeted Fluorescent Probe for Bioimaging and Food Safety Assessment.

The equilibrium state of hydrogen sulfide (H2S), a gaseous signaling molecule produced by lysosomal metabolites, in vivo is crucial for cellular function. Abnormal fluctuations in H2S concentration can interfere with the normal function of lysosomes, which has been closely linked to the pathogenesis of a variety of diseases. In view of this, a novel fluorescent probe Lyso-DPP based on 1,3,5-triarylpyrazolines was developed for the precise detection of H2S in lysosomes by using the hydrophilic morpholine moiety as a lysosomal targeting unit, and 2,4-dinitroanisole as a fluorescence-quenching and H2S-responsive unit. The probe cleverly combines the advantages of simple synthesis, sensitive blue fluorescence turn-on with a limit of detection, LOD, of 97.3 nM, good stability, and fast response time (10 min), which makes Lyso-DPP successful in portable monitoring of meat freshness in the form of test strips. Moreover, the excellent biocompatibility and precise targeting capability of the probe Lyso-DPP make it perform well in the monitoring of H2S in lysosomes, living cells, and zebrafish. This work not only provides new technical tools for food quality control but also paves up new ideas for early diagnosis and treatment of H2S-related diseases.