Promising anti-ovarian aging herbal formulation He's Yangchao promotes in vitro maturation of oocytes from advanced maternal age mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Marveled at the discovery of artemisinin, the world's expectations for traditional Chinese medicine are rising. He's Yangchao formula (HSYC) is a traditional Chinese herbal formula with the effects of tonifying kidney and essence, and reconciling yin and yang. It has been clinically proven to have anti-ovarian aging effects. Age is the primary cause of diminished ovarian reserve and assisted reproductive failure in women, whether HSYC has the potential to improve in vitro maturation of oocytes from advanced maternal age (AMA) mice has yet to be determined. AIM OF THE STUDY: This study aims to evaluate the efficacy and possible mechanism of HSYC in promoting in vitro maturation of oocytes from AMA mice. MATERIALS AND METHODS: The GV oocytes were obtained from young and aged mice. The GV oocytes from young mice were cultured in drops of M16 medium, and the GV oocytes from AMA mice were randomly divided four groups: Vehicle group (cultured in 90% M16 medium +10% blank serum), Low HSYC group (cultured in 90% M16 medium + 10% Low HSYC-medicated serum), High-HSYC group (cultured in 90% M16 medium +10% High HSYC-medicated serum), and Quercetin group (cultured in M16 medium supplemented with 10 µM quercetin). The rates of first polar body extrusion, reactive oxygen species (ROS), intracellular calcium, and mitochondrial membrane potential levels in each groups were observed. In addition, expression levels of mitochondrial function, autophagy, DNA damage, and antioxidant-related proteins were assessed. RESULTS: Supplementation of HSYC in vitro alleviated age-associated meiotic progression defects in maternally aged oocytes. Importantly, HSYC supplementation eliminated the age-related ROS accumulation to suppress DNA damage and autophagy during the in vitro maturation of maternally aged oocytes. Meanwhile, the mitochondrial function was improved after HSYC treatment, as manifested by higher mitochondrial membrane potential and lower Ca2+ levels. Furthermore, we found that HSYC supplementation during in vitro maturation of maternally aged oocytes upregulated the expression level of SIRT3, a crucial protein in regulating mitochondrial function. Consistently, the expression levels of the SOD2, PCG1α, and TFAM were increased, while the SOD2 acetylation level was decreased, which further proved its antioxidant function. CONCLUSIONS: HSYC supplementation promotes in vitro maturation of oocytes from AMA mice mainly via improving mitochondrial function and alleviating oxidative stress. The mechanism may be related to the regulation of SIRT3-dependent deacetylation of the SOD2 pathway.

Chronic environmentally relevant concentration of copper exposure induces intestinal oxidative stress, inflammation, and microbiota disturbance in freshwater grouper (Acrossocheilus fasciatus).

The influence of chronic environmentally relevant concentration of Cu2+ exposure on fish intestinal health has been rarely studied. In the present study, freshwater grouper (Acrossocheilus fasciatus) was subjected to 0 (control), 0.01 mg/L Cu2+ (Cu0.01), and 0.04 mg/L Cu2+ (Cu0.04) for 30 days. The Cu0.04 group obtained a significantly reduced survival rate, weight gain, and feed intake compared to the control group (P < 0.05). Both levels of Cu2+ exposure induced oxidative stress, evidenced by increased antioxidant enzymes' activities and malondialdehyde (MDA) contents in the intestine and serum. Based on 16S rDNA analysis, both levels of Cu2+ exposure significantly reduced intestinal microbiota community richness. In the Cu2+ exposure groups, Firmicutes/Bacteroidota ratio, and potentially pathogenic bacteria, such as Proteobacteria, genus Pseudomonas, Citrobacter, Shinella, and Aeromonas were enriched. Meanwhile, the richness of probiotic bacteria, such as Fusobacteriota, Planctomycetota, Cetobacterium, Gemmobacter, and Gemmata were significantly reduced by Cu2+ exposure. Both levels of Cu2+ exposure significantly reduced villus length, lamina propria width, and muscular thickness in the foregut and hindgut, but increased intestinal goblet cell numbers. 0.04 mg/L Cu2+ exposure significantly upregulated superoxide dismutase (sod), pro-inflammation genes nuclear factor kappa b subunit 1 (nfκb1) and interleukin 1 beta (il1ß) expression, but downregulated anti-inflammation gene transforming growth factor beta 1 (tgfß1) expression. In summary, chronic environmentally relevant concentrations of Cu2+ exposure induced intestinal oxidative stress, inflammation, prevalence of pathogen and inhibition of probiotic bacteria, and damage intestinal integrity of freshwater grouper.

Downregulation of RCN1 promotes pyroptosis in acute myeloid leukemia cells.

Reticulocalbin-1 (RCN1) is expressed aberrantly and at a high level in various tumors, including acute myeloid leukemia (AML), yet its impact on AML remains unclear. In this study, we demonstrate that RCN1 knockdown significantly suppresses the viability of bone marrow mononuclear cells (BMMNCs) from AML patients but does not affect the viability of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs) from healthy donors in vitro. Downregulation of RCN1 also reduces the viability of AML cell lines. Further studies showed that the RCN1 knockdown upregulates type I interferon (IFN-1) expression and promotes AML cell pyroptosis through caspase-1 and gasdermin D (GSDMD) signaling. Deletion of the mouse Rcn1 gene inhibits the viability of mouse AML cell lines but not the hematopoiesis of mouse bone marrow. In addition, RCN1 downregulation in human AML cells significantly inhibited tumor growth in the NSG mouse xenograft model. Taken together, our results suggest that RCN1 may be a potential target for AML therapy.

Protocol to capture transcription factor-mediated 3D chromatin interactions using affinity tag-based BL-HiChIP.

Pioneer transcription factors (TFs) can directly establish higher-order chromatin interactions to instruct gene transcription. Here, we present a protocol for capturing TF-mediated 3D chromatin interactions using affinity tag-based bridge linker (BL)-Hi-chromatin immunoprecipitation (HiChIP). We describe steps for constructing FLAG-tagged TF, performing BL-HiChIP, and preparing the library. We then detail procedures for sequencing, data analysis, and quality control. This protocol has potential applications in 3D chromatin analysis centered on any specific TF in any type of cells without the need of optimal antibodies. For complete details on the use and execution of this protocol, please refer to Ren et al. (2022).1.

Clinical application of superselective transarterial embolization of renal tumors in zero ischaemia robotic-assisted laparoscopic partial nephrectomy.

Objective: To assess the feasibility and safety of zero ischaemia robotic-assisted laparoscopic partial nephrectomy (RALPN) after preoperative superselective transarterial embolization (STE) of T1 renal cancer. Methods: We retrospectively analyzed the data of 32 patients who underwent zero ischaemia RALPN after STE and 140 patients who received standard robot-assisted laparoscopic partial nephrectomy (S-RALPN). In addition, we selected 35 patients treated with off-clamp RALPN (O-RALPN) from September 2017 to March 2022 for comparison. STE was performed by the same interventional practitioner, and zero ischaemia laparoscopic partial nephrectomy (LPN) was carried out by experienced surgeon 1-12 hours after STE. The intraoperative data and postoperative complications were recorded. The postoperative renal function, routine urine test, urinary Computed Tomography (CT), and preoperative and postoperative glomerular filtration rate (GFR) data were analyzed. Results: All operations were completed successfully. There were no cases of conversion to opening and no deaths. The renal arterial trunk was not blocked. No blood transfusions were needed. The mean operation time was 91.5 ± 34.28 minutes. The mean blood loss was 58.59 ± 54.11 ml. No recurrence or metastasis occurred. Conclusion: For patients with renal tumors, STE of renal tumors in zero ischaemia RALPN can preserve more renal function, and it provides a safe and feasible surgical method.

Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway.

Currently, the effect and molecular mechanism of calycosin, the main active ingredient of Qinshi Simiao San, which can alleviate chronic prostatitis (CP), on CP remain unclear. This study aimed to elucidate the potential mechanism of action of calycosin in CP in a rat CP model. The prostate tissue morphology was evaluated based on hematoxylin-eosin staining. Enzyme-linked immunosorbent assay was conducted to evaluate inflammatory cytokine and immune factor levels (secretory immunoglobulin A [SIgA]; immunoglobulin G [IgG]) in prostate tissues and serum. Additionally, representative biomarkers of oxidative stress, including malondialdehyde, superoxide dismutase, and catalase were detected using detection kits, and reactive oxygen species release was evaluated using immunofluorescence staining. Furthermore, the p38 mitogen-activated protein kinase (p38MAPK)/NF-kappaB (NF-κB) signaling pathway was analyzed by western blotting. The results showed that calycosin substantially ameliorated the pathological damage to prostate tissues of the CP rats. Moreover, calycosin significantly downregulated interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha, IgG, and SIgA levels. Furthermore, we found that calycosin considerably suppressed oxidative stress and inhibited the activation of the p38MAPK/NF-κB signaling pathway in rats with CP. In summary, our findings revealed that calycosin protects against CP in rats by inhibiting the p38MAPK/NF-κB pathway.

A fluorescence-based assay for Trichomonas vaginalis drug screening.

BACKGROUND: The emergence and spread of drug resistance in Trichomonas vaginalis parasites has become an important concern in trichomoniasis treatment. Fast and reliable growth assessment is critical for validating in vitro drug susceptibility and high-throughput screening of newly developed drugs. METHODS: Modified media without yeast extract were evaluated for their ability to support the growth of T. vaginalis parasites. The potential of the nucleic acid-binding dye SYBR Green I for detecting T. vaginalis drug resistance was characterized, and seeding parasite concentration and incubation time were optimized. The fluorescence assay based on SYBR Green I was further validated in four T. vaginalis isolates with different susceptibilities to the antibiotics metronidazole, tinidazole, ornidazole and secnidazole, and compared with the traditional method that detects minimum lethal concentrations (MLCs). RESULTS: A modified medium consisting of RPMI 1640 and Tryptone Plus as replacements for yeast extract and tryptone, respectively, in traditional trypticase-yeast extract-maltose (TYM) medium exhibited similar performance as TYM medium in maintaining T. vaginalis growth, while it showed much lower background fluorescent signals. The T. vaginalis SYBR Green I-based fluorescence (TSF) drug assay was found to have to satisfy one of two conditions to demonstrate the 50% inhibitory concentration of metronidazole for the sensitive isolate TV-334: (i) a seeding density of 3 × 104 parasites/ml and an incubation time of 48 h; or (ii) a seeding density of 1 × 104 parasites/ml and an incubation time of 72 h. Subsequent validation experiments revealed that the 48-h incubation/3 × 104 parasites/ml seeding density condition had a greater sensitivity to detect drug resistance than the 72-h condition. The TSF assay also exhibited high efficiency in identifying parasite drug resistance, as evidenced by its strong correlation with the standard MLC assay results (P = 0.003). CONCLUSIONS: This study presents a robust TSF assay that has the potential to facilitate high-throughput, automated in vitro anti-trichomoniasis susceptibility testing for drug resistance monitoring and drug development. In comparison to the standard MLC method, this assay offers the advantages of reduced labor and elimination of subjective examination.

Electrochemically Responsive 3d Nanoarchitectures.

Responsive nanomaterials are being developed to create new unique functionalities such as switchable colours and adhesive properties or other programmable features in response to external stimuli. While many existing examples rely on changes in temperature, humidity, or pH, we aim to explore an alternative approach relying on simple electric input signals. More specifically, we develop three-dimensional (3D) electrochromic architected microstructures using carbon nanotube (CNT) - Tin (Sn) composites that can be reconfigured by lithiating Sn with low power electric input (≈ 50 nanowatts). These microstructures have a continuous, regulated, and non-volatile actuation determined by the extent of the electrochemical lithiation process. In addition, our proposed fabrication process relies only on batch lithographic techniques, enabling the parallel production of thousands of 3D microstructures. We demonstrate structures with a 30%-97% change in open-end area upon actuation and highlight the importance of geometric factors in the response and structural integrity of 3D architected microstructures during electrochemical actuation. This article is protected by copyright. All rights reserved.

Silicon-Cantilever-Enhanced Single-Fiber Photoacoustic Acetylene Gas Sensor.

A single-fiber photoacoustic (PA) sensor with a silicon cantilever beam for trace acetylene (C2H2) gas analysis was proposed. The miniature gas sensor mainly consisted of a microcantilever and a non-resonant PA cell for the real-time detection of acetylene gas. The gas diffused into the photoacoustic cell through the silicon cantilever beam gap. The volume of the PA cell in the sensor was about 14 µL. By using a 1 × 2 fiber optical coupler, a 1532.8 nm distributed feedback (DFB) laser and a white light interference demodulation module were connected to the single-fiber photoacoustic sensor. A silicon cantilever was utilized to improve the performance when detecting the PA signal. To eliminate the interference of the laser-reflected light, a part of the Fabry-Perot (F-P) interference spectrum was used for phase demodulation to achieve the highly sensitive detection of acetylene gas. The minimum detection limit (MDL) achieved was 0.2 ppm with 100 s averaging time. In addition, the calculated normalized noise equivalent absorption (NNEA) coefficient was 4.4 × 10-9 W·cm-1·Hz-1/2. The single-fiber photoacoustic sensor designed has great application prospects in the early warning of transformer faults.

Anchoring Π-D Conjugated Metal-Organic Frameworks with Dual-Active Centers on Carbon Nanotubes for Advanced Potassium-Ion Batteries.

Potassium-ion batteries (PIBs) are gradually gaining attention owing to their natural abundance, excellent security, and high energy density. However, developing excellent organic cathode materials for PIBs to overcome the poor cycling stability and slow kinetics caused by the large radii of K+ ions is challenging. This study demonstrates for the first time the application of a hexaazanonaphthalene (HATN)-based two-dimensional π-d conjugated metal-organic framework (2D c-MOF) with dual-active centers (Cu-HATNH) and integrates Cu-HATNH with carbon nanotubes (Cu-HATNH@CNT) as the cathode material for PIBs. Owing to this systematic module integration and more exposed active sites with high utilization, Cu-HATNH@CNT exhibited a high initial capacity (317.5 mA h g-1 at 0.1 A g-1 ), excellent long-term cycling stability (capacity retention of 96.8% at 5 A g-1 after 2200 cycles), and outstanding rate capacity (147.1 mA h g-1 at 10 A g-1 ). The reaction mechanism and performance  were determined by combining experimental characterization and density functional theory (DFT) calculations. This contribution provides new opportunities for designing high-performance 2D c-MOF cathodes with multiple active sites for PIBs. This article is protected by copyright. All rights reserved.

Health Behaviors, Financial Difficulties, and Depressive Symptoms Among Older Adults Across Gender and Race During the COVID-19 Pandemic.

Background: COVID-19 deeply affected the health and well-being of older adults. This study examines health behavior change and the interrelationships between health behaviors, financial difficulties, and depressive symptoms among older adults across gender and race during the pandemic. Methods: Using Rounds 1, 5, and 10 of the National Health and Aging Trends Study (NHATS) linked with the NHATS COVID-19 dataset, our sample included Medicare beneficiaries aged 65 or older in the U.S. (N = 3,118). We modeled the interrelationships between health behaviors, financial difficulties, and depressive symptoms using a structural equation model. Results: Female participants reported less walking, more changes in eating habits, less sleeping, and less alcohol consumption during the pandemic than before the pandemic compared to male participants. Compared to White, Non-White participants showed higher proportions of experiencing financial difficulties, less walking, less vigorous activity, and changes in time spent eating and sleeping during than before the pandemic. Financial difficulties was positively associated with depressive symptoms and sedentary behavior. Active behavior was negatively associated with depressive symptoms, while sedentary behavior was positively associated with more depressive symptoms. Discussion: Health professionals should consider health behaviors and financial difficulties when intervening on depressive symptoms experienced by older adults since the pandemic.

Berberine-loaded MSC-derived sEVs encapsulated in injectable GelMA hydrogel for spinal cord injury repair.

After spinal cord injury (SCI), local inflammatory response and fibrous scar formation severely hinder nerve regeneration. Berberine (Ber) has a powerful regulatory effect on the local microenvironment, but its limited solubility and permeability through the blood-brain barrier severely limit its systemic efficacy. Human umbilical cord mesenchymal stem cells (hUC-MSCs)-derived small extracellular vesicles (sEVs) are natural nanocarriers with high cargo loading capacity, and can cross the blood-brain barrier. Most importantly, sEVs can improve drug solubility and drug utilization. Therefore, they can overcome many defects of Ber application. This experiment aimed to design a Ber-carrying hUC-MSCs-derived sEVs and GelMA hydrogel. Ber was loaded into sEVs (sEVs-Ber) by ultrasonic co-incubation with a drug loading capacity (LC) of 15.07%. The unhindered release of up to 80% of sEVs-Ber from GelMA hydrogel was accomplished for up to 14 days. And they could be directly absorbed by local cells of injury, allowing for direct local delivery of the drug and enhancing its efficacy. The experimental results confirmed injecting GelMA-sEVs-Ber into spinal cord defects could exert anti-inflammatory effects by regulating the expression of inflammatory factors. It also demonstrated the anti-fibrotic effect of Ber in SCI for the first time. The modulatory effects of sEVs and Ber on the local microenvironment significantly promoted nerve regeneration and recovery of motor function in post-SCI rats. These results demonstrated that the GelMA-sEVs-Ber dual carrier system is a promising therapeutic strategy for SCI repair.

Characterization of Vps13b-mutant mice reveals neuroanatomical and behavioral phenotypes with females less affected.

The vacuolar protein sorting-associated protein 13B (VPS13B) is a large and highly conserved protein. Disruption of VPS13B causes the autosomal recessive Cohen syndrome, a rare disorder characterized by microcephaly and intellectual disability among other features, including developmental delay, hypotonia, and friendly-personality. However, the underlying mechanisms by which VPS13B disruption leads to brain dysfunction still remain unexplained. To gain insights into the neuropathogenesis of Cohen syndrome, we systematically characterized brain changes in Vps13b-mutant mice and compared murine findings to 235 previously published and 17 new patients diagnosed with VPS13B-related Cohen syndrome. We showed that Vps13b is differentially expressed across brain regions with the highest expression in the cerebellum, the hippocampus and the cortex with postnatal peak. Half of the Vps13b-/- mice die during the first week of life. The remaining mice have a normal lifespan and display the core phenotypes of the human disease, including microcephaly, growth delay, hypotonia, altered memory, and enhanced sociability. Systematic 2D and 3D brain histo-morphological analyses reveal specific structural changes in the brain starting after birth. The dentate gyrus is the brain region with the most prominent reduction in size, while the motor cortex is specifically thinner in layer VI. The fornix, the fasciculus retroflexus, and the cingulate cortex remain unaffected. Interestingly, these neuroanatomical changes implicate an increase of neuronal death during infantile stages with no progression in adulthood suggesting that VPS13B promotes neuronal survival early in life. Importantly, whilst both sexes were affected, some neuroanatomical and behavioral phenotypes were less pronounced or even absent in females. We evaluate sex differences in Cohen patients and conclude that females are less affected both in mice and patients. Our findings provide new insights about the neurobiology of VPS13B and highlight previously unreported brain phenotypes while defining Cohen syndrome as a likely new entity of non-progressive infantile neurodegeneration.

The phospholipase effector Tle1Vc promotes Vibrio cholerae virulence by killing competitors and impacting gene expression.

Vibrio cholerae utilizes the Type VI secretion system (T6SS) to gain an advantage in interbacterial competition by delivering anti-prokaryotic effectors in a contact-dependent manner. However, the impact of T6SS and its secreted effectors on physiological behavior remains poorly understood. In this study, we present Tle1Vc, a phospholipase effector in atypical pathogenic V. cholerae E1 that is secreted by T6SS via its interaction with VgrG1E1. Tle1Vc contains a DUF2235 domain and belongs to the Tle1 (type VI lipase effector) family. Bacterial toxicity assays, lipase activity assays and site-directed mutagenesis revealed that Tle1Vc possessed phospholipase A1 activity and phospholipase A2 activity, and that Tle1Vc-induced toxicity required a serine residue (S356) and two aspartic acid residues (D417 and D496). Cells intoxication with Tle1Vc lead to membrane depolarization and alter membrane permeability. Tli1tox-, a cognate immunity protein, directly interacts with Tle1Vc to neutralize its toxicity. Moreover, Tle1Vc can kill multiple microorganisms by T6SS and promote in vivo fitness of V. cholerae through mediating antibacterial activity. Tle1Vc induces bacterial motility by increasing the expression of flagellar-related genes independently of functional T6SS and the tit-for-tat (TFT) response, where Pseudomonas aeruginosa uses its T6SS-H1 cluster to counterattack other offensive attackers. Our study also demonstrated that the physical puncture of E1 T6SS can induce a moderate TFT response, which is essential to the Tle1Vc-mediated strong TFT response, maximizing effector functions. Overall, our study characterized the antibacterial mechanism of phospholipase effector Tle1Vc and its multiple physiological significance.

Ocular manifestations of mitochondrial neurogastrointestinal encephalomyopathy: A case report and literature review.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive multisystem disorder that often presents with gastrointestinal and neurological symptoms. Here we report a 33-year-old male who presented with a 16-year history of diarrhea with black stool and progressive weight loss. He complained of progressive bilateral blurred vision, upper eyelids heaviness, ocular motility impairment, and color blindness. Peripheral neuropathy, bilateral sensorineural deafness, hyperlactatemia, diabetes mellitus, hepatic steatosis, blood coagulation dysfunction, and diffuse leukoencephalopathy were detected in the systemic evaluation. Based on the novel homozygous pathogenic variant in the TYMP gene (c.1159+1G>A), he was diagnosed with MNGIE. On ophthalmic examinations, the thickness of the inner retina and ganglion cell complex significantly decreased. ERG showed diffusely decreased amplitudes. The electronegative electroretinogram, which was first reported in MNGIE, indicated a more severe inner retina impairment. The bilateral papillomacular bundle defect and central vision loss in MNGIE are consistent with classical mitochondrial optic neuropathies' features. According to the literature, pigmentary retinopathy, optic neuropathy, and abnormal pupillary reflexes are uncommon ocular features of MNGIE. This study contributes to a better understanding of ocular manifestations in MNGIE and demonstrates that MNGIE may have dyschromatopsia and an electronegative electroretinogram.

Molecular mechanisms that regulate the heat stress response in sea urchins (Strongylocentrotus intermedius) by comparative heat tolerance performance and whole-transcriptome RNA sequencing.

In the context of climate change and extreme high temperature, the commercially important sea urchin Strongylocentrotus intermedius suffers high mortality during summer in Northern China. How sea urchins respond to high temperatures is of great concern to academia and industry. How to understand the heat tolerance of sea urchin from the whole transcriptome level. In this study, the heat-resistant S. intermedius bred by our team and its control group were used as the research objects, then we applied whole-transcriptome RNA sequencing to detect differentially expressed mRNAs, microRNAs, long noncoding RNAs that respond to heat stress in the heat-resistant and control S. intermedius. A competitive endogenous RNA (ceRNA) regulatory network was constructed with predicted pairs of differentially expressed mRNAs and noncoding RNAs and revealed the molecular regulatory mechanisms in S. intermedius responding to heat stress. A functional analysis suggested that the ceRNAs were involved in basal metabolism, calcium ion transport, endoplasmic reticulum stress, and apoptosis. This is the whole-transcriptomic analysis of S. intermedius under heat stress to propose ceRNA networks that will provide a basis for studying the potential functions of long noncoding RNAs and miRNAs in the heat stress response in S. intermedius and provide a theoretical basis for the study of the molecular mechanism of sea urchins in response to environmental changes.

The Anticancer Effect of Napabucasin (BBI608), a Natural Naphthoquinone.

Napabucasin (also known as BBI608) is a natural naphthoquinone originally identified as a cancer cell stemness inhibitor. Accumulated in vitro and in vivo evidence demonstrated that napabucasin showed significant anticancer effects in various types of cancers. Napabucasin inhibits cancer cell proliferation, induces apoptosis and cell cycle arrest, and suppresses metastasis and relapse. Such anticancer activities of napabucasin mainly rely on the inhibition of cancer stemness by targeting signal transducer and activator of transcription 3 (STAT3) and its related gene inhibition. However, several novel molecular targets for napabucasin, such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and thioredoxin reductase 1 (TrxR1), have been reported. Napabucasin represents a promising anticancer lead for multiple cancers. In this mini review, the anticancer potential and the molecular mechanism of napabucasin will be briefly highlighted.

Synthesis and Biological Evaluation of Novel 2-Amino-1,4-Naphthoquinone Amide-Oxime Derivatives as Potent IDO1/STAT3 Dual Inhibitors with Prospective Antitumor Effects.

Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for cancer therapy. In this study, we synthesized three novel 2-amino-1,4-naphthoquinone amide-oxime derivatives and identified them as dual inhibitors of IDO1 and STAT3. The representative compound NK3 demonstrated effective binding to IDO1 and exhibited good inhibitory activity (hIDO1 IC50 = 0.06 µM), leading to its selection for further investigation. The direct interactions between compound NK3 and IDO1 and STAT3 proteins were confirmed through surface plasmon resonance analysis. A molecular docking study of compound NK3 revealed key interactions between NK3 and IDO1, with the naphthoquinone-oxime moiety coordinating with the heme iron. In the in vitro anticancer assay, compound NK3 displayed potent antitumor activity against selected cancer cell lines and effectively suppressed nuclear translocation of STAT3. Moreover, in vivo assays conducted on CT26 tumor-bearing Balb/c mice and an athymic HepG2 xenograft model revealed that compound NK3 exhibited potent antitumor activity with low toxicity relative to 1-methyl-L-tryptophan (1-MT) and doxorubicin (DOX). Overall, these findings provided evidence that the dual inhibitors of IDO1 and STAT3 may offer a promising avenue for the development of highly effective drug candidates for cancer therapy.

Prominent Josephson tunneling between twisted single copper oxide planes of Bi2Sr2-xLaxCuO6+y.

Josephson tunneling in twisted cuprate junctions provides a litmus test for the pairing symmetry, which is fundamental for understanding the microscopic mechanism of high temperature superconductivity. This issue is rekindled by experimental advances in van der Waals stacking and the proposal of an emergent d+id-wave. So far, all experiments have been carried out on Bi2Sr2CaCu2O8+x (Bi-2212) with double CuO2 planes but show controversial results. Here, we investigate junctions made of Bi2Sr2-xLaxCuO6+y (Bi-2201) with single CuO2 planes. Our on-site cold stacking technique ensures uncompromised crystalline quality and stoichiometry at the interface. Junctions with carefully calibrated twist angles around 45° show strong Josephson tunneling and conventional temperature dependence. Furthermore, we observe standard Fraunhofer diffraction patterns and integer Fiske steps in a junction with a twist angle of 45.0±0.2°. Together, these results pose strong constraints on the d or d+id-wave pairing and suggest an indispensable isotropic pairing component.