Charge Transfer and Intersystem Crossing in Compact Naphthalenediimide-Phenothiazine Triads: Synthesis and Study of the Photophysical Property with Transient Optical and Electron Paramagnetic Resonance Spectroscopic Methods.

In order to obtain a long-lived charge separation (CS) state in compact electron donor-acceptor molecular systems, we prepared a series of naphthalenediimide (NDI)-phenothiazine (PTZ) triads, with phenylene as the linker between the donor and acceptor. Conformation restriction is imposed to control the mutual orientation of the NDI and PTZ units by attaching methyl groups on the phenylene linker to tune the electronic coupling between the donor and the acceptor. Moreover, the PTZ moiety was oxidized to sulfoxide to tune the ordering of the CS state and the 3LE state (LE: locally excited state). UV-vis absorption spectra indicate electronic coupling between NDI with the phenylene linker as well as the PTZ units, manifested by the appearance of a charge-transfer (CT) absorption band, whereas this coupling is devoid in the triads with conformation restriction imposed. Fluorescence is strongly quenched in the triads compared to the reference compound, indicating electron transfer upon photoexcitation. Femtosecond transient absorption spectra indicate that the CS takes 0.8 ps, and then the 3LE state is formed by charge recombination in 83 ps. Nanosecond transient absorption (ns-TA) spectra show that the 3NDI state was observed in nonpolar solvents such as cyclohexane (triplet state lifetime: 95.7 µs), whereas the CS state was observed in more polar solvents. The CS state lifetimes are up to 1.2 µs (in toluene). Time-resolved electron paramagnetic resonance spectra of the triads in toluene consist of two types of signals: CS states (narrower signals, ∼10 mT) and 3LE states (broader signals, ∼50 to 200 mT). In the spectra of the triads containing PTZ, the CS state signals dominate, whereas for the triads containing oxidized PTZ, the 3NDI signals (zero-field splitting D ≈ 2000 MHz) prevail, both observations being in agreement with the ns-TA spectral studies. The electron spin polarization phase pattern of the 3NDI states of the triads indicates that the intersystem crossing (ISC) mechanism is spin-orbit charge-transfer ISC. Considering the 3CS state as ion pairs, the electron-exchange energy (J) is determined to be -39 to -59 MHz, and the electron spin dipolar interaction is 83-92 MHz.

The Identification of Oral Cariogenic Bacteria through Colorimetric Sensor Array Based on Single-Atom Nanozymes.

Effective identification of multiple cariogenic bacteria in saliva samples is important for oral disease prevention and treatment. Here, a simple colorimetric sensor array is developed for the identification of cariogenic bacteria using single-atom nanozymes (SANs) assisted by machine learning. Interestingly, cariogenic bacteria can increase oxidase-like activity of iron (Fe)─nitrogen (N)─carbon (C) SANs by accelerating electron transfer, and inversely reduce the activity of Fe─N─C further reconstruction with urea. Through machine-learning-assisted sensor array, colorimetric responses are developed as "fingerprints" of cariogenic bacteria. Multiple cariogenic bacteria can be well distinguished by linear discriminant analysis and bacteria at different genera can also be distinguished by hierarchical cluster analysis. Furthermore, colorimetric sensor array has demonstrated excellent performance for the identification of mixed cariogenic bacteria in artificial saliva samples. In view of convenience, precise, and high-throughput discrimination, the developed colorimetric sensor array based on SANs assisted by machine learning, has great potential for the identification of oral cariogenic bacteria so as to serve for oral disease prevention and treatment.

A bifunctional Pasteurella multocida ß1-3-galactosyl/N-acetylgalactosaminyltransferase (PmNatB) for the highly efficient chemoenzymatic synthesis of disaccharides.

Glycosyltransferases are nature's key biocatalysts for the formation of glycosidic bonds. Discovery and characterization of new synthetically useful glycosyltransferases are critical for the development of efficient enzymatic and chemoenzymatic strategies for producing complex carbohydrates and glycoconjugates. Herein we report the identification of Pasteurella multocida PmNatB as a bifunctional single-catalytic-domain glycosyltransferase with both ß1-3-galactosyltransferase and ß1-3-N-acetylgalactosaminyltransferase activities. It is a novel glycosyltransferase for constructing structurally diverse GalNAcß3Galα/ßOR and Galß3GalNAcα/ßOR disaccharides in one-pot multienzyme systems with in situ generation of UDP-sugars.

Taxus chinensis var. mairei (Lemée et Lévl) Cheng et L.K. Fu overcomes the resistance to osimertinib in EGFR-mutant non-small-cell lung cancer via suppression of ERK1/2-related cholesterol biosynthesis.

ETHNOPHARMACOLOGICAL RELEVANCE: Acquired resistance to osimertinib limits its clinical efficacy in non-small cell lung cancer (NSCLC) with EGFR mutations. The widespread recognition of Taxus chinensis var. Mairei (Lemée et Lévl) Cheng et L.K. Fu (Chinese yew) as a natural anti-cancer medication is well-established. However, the specific contribution of Taxus chinensis var. Mairei (Lemée et Lévl) Cheng et L.K. Fu in addressing resistance to osimertinib is still uncertain. AIM OF THE STUDY: Based on the biological behaviors and lipid metabolism, we investigated whether aqueous extract of Taxus chinensis var. Mairei (Lemée et Lévl) Cheng et L.K. Fu (AETC) could enhance the antitumor effect of osimertinib in NSCLC with an investigation on the precise mechanisms. MATERIALS AND METHODS: The effect of AETC on enhancing osimertinib sensitivity was assessed via cell viability measurements, levels of reactive oxygen species (ROS), apoptosis, and lipid levels. Western blotting was used to verify the mechanisms of AETC responsible for overcoming the resistance to osimertinib via ERK1/2 overexpression and knockdown models. In vivo validation was conducted using subcutaneous xenografts from osimertinib-resistant cells in nude mice. RESULTS: Osimertinib-resistant cells exhibited altered cholesterol biosynthesis, which was induced by ERK1/2 activation. The combination of AETC and osimertinib can synergistically decrease the levels of ROS in cells, enhance apoptosis, and inhibit the growth of osimertinib-resistant cells. Mechanistic experiments demonstrated that AETC can downregulate the key regulators of cholesterol biosynthesis by regulating ERK1/2, inhibiting the endogenous synthesis rate of cholesterol, and suppressing the level of lipids in osimertinib-resistant cells and xenograft tumors when combined with osimertinib, ultimately reversing resistance to osimertinib. CONCLUSIONS: The resistance to osimertinib is significantly influenced by cholesterol biosynthesis, highlighting its pivotal role in this context. AETC can enhance osimertinib sensitivity via ERK/SREBP-2/HMGCR-mediated cholesterol biosynthesis. These results provide a promising therapeutic target and potential treatment option for resistance to osimertinib.

Clofazimine inhibits innate immunity against Mycobacterium tuberculosis by NF-κB.

Tuberculosis (TB) remains one of the infectious diseases with high incidence and high mortality. About a quarter of the population has been latently infected with Mycobacterium tuberculosis. At present, the available TB treatment strategies have the disadvantages of too long treatment duration and serious adverse reactions. The sustained inflammatory response leads to permanent tissue damage. Unfortunately, the current selection of treatment regimens does not consider the immunomodulatory effects of various drugs. In this study, we preliminarily evaluated the effects of commonly used anti-tuberculosis drugs on innate immunity at the cellular level. The results showed that clofazimine (CFZ) has a significant innate immunosuppressive effect. CFZ significantly inhibited cytokines and type I interferons (IFNα and IFNß) expression under both lipopolysaccharide stimulation and CFZ-resistant strain infection. In further mechanistic studies, CFZ strongly inhibited the phosphorylation of nuclear factor kappa B (NF-κB) p65 and had no significant effect on the phosphorylation of p38. In conclusion, our study found that CFZ suppresses innate immunity against Mycobacterium tuberculosis by NF-κB, which should be considered in future regimen development. IMPORTANCE: The complete elimination of Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, from TB patients is a complicated process that takes a long time. The excessive immune inflammatory response of the host for a long time causes irreversible organic damage to the lungs and liver. Current antibiotic-based treatment options involve multiple complex drug combinations, often targeting different physiological processes of Mtb. Given the high incidence of post-tuberculosis lung disease, we should also consider the immunomodulatory properties of other drugs when selecting drug combinations.

Efficient degradation of sulfadiazine by UV-triggered electron transfer on oxalic acid-functionalized corn straw biochar for activating peroxyacetic acid: Performance, mechanism, and theoretical calculation.

A novel UV/oxalic acid functionalized corn straw biochar (OCBC)/peroxyacetic acid (PAA) system was built to degrade sulfadiazine from waters. 94.7 % of SDZ was removed within 30 min by UV/OCBC/PAA. The abundant surface functional groups and persistent free radicals (PFRs) on OCBC were responsible for these performances. Cyclic voltammetry (CV) and other characterization analysis revealed, under UV irradiation, the addition of OCBC served as electron donor, which might promote the reaction of electrons with PAA. The quenching and electron paramagnetic resonance (EPR) tests indicated that R-O•, 1O2 and •OH were generated. Theoretical calculations indicated sulfonamide bridge was vulnerable under the attacks of reactive species. In addition, high removal effect achieved by 5 reuse cycles and different real waters also suggested the sustainability of UV/OCBC/PAA. Overall, this study provided a feasible approach to remove SDZ with high mineralization efficiency, in addition to a potential strategy for resource utilization of corn straw.

The Function and Mechanism of Long Noncoding RNAs in Adipogenic Differentiation.

Adipocytes are crucial for maintaining energy balance. Adipocyte differentiation involves distinct stages, including the orientation stage, clone amplification stage, clone amplification termination stage, and terminal differentiation stage. Understanding the regulatory mechanisms governing adipogenic differentiation is essential for comprehending the physiological processes and identifying potential biomarkers and therapeutic targets for metabolic diseases, ultimately improving glucose and fat metabolism. Adipogenic differentiation is influenced not only by key factors such as hormones, the peroxisome proliferator-activated receptor (PPAR) family, and the CCATT enhancer-binding protein (C/EBP) family but also by noncoding RNA, including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA). Among these, lncRNA has been identified as a significant regulator in adipogenic differentiation. Research has demonstrated various ways in which lncRNAs contribute to the molecular mechanisms of adipogenic differentiation. Throughout the adipogenesis process, lncRNAs modulate adipocyte differentiation and development by influencing relevant signaling pathways and transcription factors. This review provides a brief overview of the function and mechanism of lncRNAs in adipogenic differentiation.

Sub-chronically exposing zebrafish to environmental levels of methomyl induces dysbiosis and dysfunction of the gut microbiota.

The widespread use of carbamate pesticides has led to numerous environmental and health concerns, including water contamination and perturbation of endocrine homeostasis among organisms. However, there remains a paucity of research elucidating the specific effects of methomyl on gut microbial composition and physiological functions. This study aimed to investigate the intricate relationship between changes in zebrafish bacterial communities and intestinal function after 56 days of sub-chronic methomyl exposure at environmentally relevant concentrations (0, 0.05, 0.10, and 0.20 mg/L). Our findings reveal significant methomyl-induced morphological changes in zebrafish intestines, characterized by villi shortening and breakage. Notably, methomyl exposure down-regulated nutrient and energy metabolism, and drug metabolism at 0.05-0.10 mg/L, while up-regulating cortisol, inflammation-related genes, and apoptotic markers at 0.20 mg/L. These manifestations indicate physiological stress imposition and disruption of gut microbiota equilibrium, impacting metabolic processes and instigating low-grade inflammatory responses and apoptotic cascades. Importantly, changes in intestinal function significantly correlated with shifts in specific bacterial taxa abundance, including Shewanella, Rubrobacter, Acinetobacter, Bacillus, Luteolibacter, Nocardia, Defluviimonas, and Bacteroides genus. In summary, our study underscores the potential adverse effects of environmental methomyl exposure on aquatic organisms, emphasizing the necessity for further research to mitigate its repercussions on environmental health and ecosystem stability.

Prediction of internal jugular vein catheter length inserted through the posterior approach of the sternocleidomastoid muscle.

This study aimed to determine an equation to estimate the optimal insertion length for catheter placement via the posterior approach of the sternocleidomastoid muscle in cancer patients. This retrospective study included patients with cancer who underwent infusion port implantation surgery in the Oncology Department of the 900th Hospital of Joint Logistic Support Force of the Chinese People Liberation Army from April 2017 to September 2023. Patient height (H), weight (W), chest length (C), and length of the internal jugular vein catheter (L) were collected from medical records. The patients were randomized 7:3 to the training and validation sets. Linear regression analyses were used in the training set to determine formulas to predict catheter length. The formula predictive value was analyzed using the Bland-Altman method in the validation set. This study included 336 patients, with a mean age of 58.27 ±â€…11.70 years, randomized in the training (n = 235) and validation (n = 101) sets. Linear regression analysis revealed that the equations for catheter length relative to H, body mass index (BMI), and C are L = 0.144 × H - 8.258 (R²â€…= 0.608, P < .001), L = -0.103 × B + 17.384 (R²â€…= 0.055, P < .001), and L = 0.477 × C + 1.769 (R²â€…= 0.342, P < .001), respectively. The multivariable linear regression analysis showed that the equation between the length of the catheter and H and C was L = 0.131 × H + 0.086 × C-8.515 (R²â€…= 0.614, P < .001). The Bland-Altman analysis in the validation set showed that the predicted values of internal jugular vein catheter length and the actual values showed good agreement. The optimal L might be determined by simple formulas based on patients H and C.

Changes in combined toxicity of benzophenone-3 and humic acid on Daphnia magna and zebrafish during chlorination disinfection process.

Conventional wastewater treatment methods cannot completely remove the ultraviolet (UV) filters or dissolved organic matter. The transformation characteristics of these substances during chlorination disinfection and the varying species-specific toxicities of their combinations remain unclear. Here, Daphnia magna and zebrafish were exposed to benzophenone-3 (BP-3) and humic acid (HA) before and after chlorination disinfection. The results from chemical indicators showed that chlorination treatment decreased UV254 values and changed the intensity of parallel factors in three-dimensional fluorescence. Based on chemical analysis, the chlorine concentration and chlorination time for the toxicity experiments were set at 5 mg/L and 6 h, respectively. Exposure to HA and BP-3 before and after chlorination decreased the heart rate (by 1.37-28.12 %) in both species. However, species-specific responses, including survival rate, swimming distance, and expression of genes related to neurodevelopment, growth, and oxidative stress, were induced by chlorination. Chlorination reduced the impact of HA exposure but worsened the effects of HA and BP-3 co-exposure on D. magna. However, in zebrafish, the toxic effects intensified in most of the exposure groups after chlorination. Correlation analysis showed that the parallel factors of three-dimensional fluorescence were correlated with toxic effects on zebrafish, whereas UV254 was more significantly correlated with toxic effects on D. magna. This study provides insights into the combined toxicity of UV filters and dissolved organic matter in different aquatic organisms during chlorination, which is useful for risk control and optimization of the chlorination process.

Sub-Chronic Methomyl Exposure Induces Oxidative Stress and Inflammatory Responses in Zebrafish with Higher Female Susceptibility.

The widespread use of carbamate pesticides has raised significant environmental and health concerns, particularly regarding water contamination and the disruption of defense systems in organisms. Despite these concerns, research on the differential impacts of pesticides on male and female organisms remains limited. This study focused on methomyl, investigating sex-specific differences in liver antioxidant defenses and inflammatory response indices in male and female zebrafish after 56 days of exposure to environmentally relevant concentrations (0, 0.05, 0.10, and 0.20 mg/L). Our findings indicate that methomyl exposure significantly increased ROS content in zebrafish livers, inducing oxidative stress and activating enzymatic antioxidant defenses such as SOD, CAT, and GSH-Px activities. Sub-chronic exposure altered the expression of apoptosis-related genes (Bax/Bcl2a and Caspases3a), resulting in liver cell apoptosis in a concentration-dependent manner, with the 0.20 mg/L concentration causing the most severe damage. Additionally, methomyl exposure at environmentally relevant concentrations triggered persistent inflammatory responses in liver tissues, evidenced by increased transcription levels of inflammatory factor genes and the activation of toll-like receptors, heightening susceptibility to exogenous allergens. It is noteworthy that oxidative damage indicators (AST, ROS, MDA) and inflammatory gene expressions (IL-1ß, TNF-α) were significantly higher in female livers compared to male livers at 0.10-0.20 mg/L methomyl exposure. Consequently, our study underscores the potential adverse effects of environmental methomyl exposure on aquatic organisms and highlights the need for heightened consideration of the risks posed by environmental endocrine disruptors to female health and safety.

Place of Birth and Cognitive Function Among Older Americans: Findings from the Harmonized Cognitive Assessment Protocol.

OBJECTIVES: Growing evidence suggests that place of birth (PoB) and related circumstances may have long-lasting and multiplicative contributions to various later-life outcomes. However, the specific contributions to different domains of cognitive function in late life remain less understood. This study investigated the extent to which state of birth contributes to a wide range of domains of later-life cognitive function. METHODS: A nationally representative sample of Americans aged 65 and older (N=3,333) from the Health and Retirement Study (HRS) Harmonized Cognitive Assessment Protocol (HCAP) was utilized. Cognitive function was assessed in HCAP and linked to HRS state of birth data to explore the contribution of PoB to later-life cognitive disparities. Regression-based Shapley decompositions were employed to quantify this contribution. RESULTS: PoB significantly contributed to all assessed cognitive domains including memory, executive function, language and fluency, visuospatial function, orientation, and general cognitive function. Geographic disparities in cognitive function were evident across PoB, with individuals born in US southern states and foreign-born individuals performing worse than those born in other states. Overall, state of birth accounted for 2.2-9.7% of the total variance in cognition after adjusting for age, sex, and race/ethnicity. This contribution declined to 2.0-7.0% after further adjusting for comprehensive socioeconomic and health factors over the life course, and were robust to the control of current state of residence. DISCUSSION: PoB has lasting contributions to later-life cognition, with significant geographic disparities observed. Addressing these disparities requires more equalized place-based policies, resources, and early-life environments to promote health equity over the life course.

Preparation of a novel type I feline coronavirus virus-like particle vaccine and its immunogenicity in mice and cats.

Feline coronavirus (FCoV) infection is a leading cause of death in cats. In this study, we produced FCoV-I virus-like particles (VLPs) containing E, M, N, and S proteins using a baculovirus expression system and mixed VLPs with the adjuvants MF59 and CpG 55.2 to prepare an VLP/MF59/CpG vaccine. After immunization of mice with the vaccine, IgG specific antibodies titers against S and N proteins increased to 1:12,800, and IFN-γ+ and IL-4+ splenocytes were significantly increased. Following immunization of FCoV-negative cats, the S protein antibodies in immunized cats (5/5) increased significantly, with a peak of 1:12,800. Notably, after booster vaccination in FCoV-positive cats, a significant reduction in viral load was observed in the feces of partial cats (4/5), and the FCoV-I negative conversion was found in two immunized cats (2/5). Therefore, the VLP/MF59/CpG vaccine is a promising candidate vaccine to prevent the FCoV infection.

Dynamic characterization of vascular response and treatment in oral traumatic ulcer in mice via photoacoustic imaging.

Background: Dynamic surveillance of vasculature is essential for evaluating the healing of oral ulcer. Existing techniques used in vascular imaging face limitations, such as inadequate spatial resolution, restricted diagnostic depth, and the necessity of exogenous contrast agents. Therefore, this study aimed to use robust photoacoustic imaging (PAI) for the dynamic monitoring of vascular response during healing and the associated treatment process of oral ulcer. Methods: Kunming mice (male, 8 weeks old, 31-41 g) were treated with 50% acetic acid for 90 s on the tongue mucosa for induction of oral traumatic ulcer. Mice were randomly divided into three groups (n=12): the control, compound chamomile and lidocaine hydrochloride gel (CCLH), and phycocyanin (PC) groups. PAI was then conducted on days 0, 2, 3, 5, and 7 to obtain vessel parameters of the ulcer area, including vessel intensity, density, mean diameter, maximum diameter, and curvature. Immunohistochemical and hematoxylin and eosin (HE) staining were performed on days 3 and 7 to assess microvessel density and inflammation score. The ulcer healing rate and body weight changes were evaluated for clinical observation. Results: Beginning on the second day after ulcer induction, there was a progressive increase over time in blood intensity and vessel parameters, including vascular density and diameter. On day 7, the CCLH and PC groups demonstrated significantly higher measures than did the control group in terms of blood intensity (P<0.05 and P<0.01), vascular density (both P values <0.05), mean diameter (both P values <0.01), and maximum diameter (P<0.01 and P<0.05). Vessel curvature in the two treatment groups exhibited no significant differences compared to that in the control group (both P values >0.05). The effects of vascular morphological changes were further supported by the histological and clinical outcomes. On day 7, compared to that of the control group, the level of microvessel density was significantly higher in both the CCLH (P<0.01) and PC (P<0.05) groups. The histopathological score in PC group was significantly lower than that of the control group on day 7 (P<0.05). Additionally, compared to that of the control group, the healing rates of the CCLH (P<0.01) and PC groups (P<0.05) were superior on day 7. On day 3, the control group showed more weight loss than did the CCLH (P<0.05) and PC (P<0.01) groups. Conclusions: These findings indicate that PAI is a valuable strategy for the dynamic and quantitative analysis of vascular alterations in oral traumatic ulcers and support its prospective application in improving clinical treatment.

Silibinin Targeting Heat Shock Protein 90 Represents a Novel Approach to Alleviate Nonalcoholic Fatty Liver Disease by Simultaneously Lowering Hepatic Lipotoxicity and Enhancing Gut Barrier Function.

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological condition characterized by intrahepatic ectopic steatosis. Due to the increase in high-calorie diets and sedentary lifestyles, NAFLD has surpassed viral hepatitis and become the most prevalent chronic liver disease globally. Silibinin, a natural compound, has shown promising therapeutic potential for the treatment of liver diseases. Nevertheless, the ameliorative effects of silibinin on NAFLD have not been completely understood, and the underlying mechanism is elusive. Therefore, in this study, we used high-fat diet (HFD)-induced mice and free fatty acid (FFA)-stimulated HepG2 cells to investigate the efficacy of silibinin for the treatment of NAFLD and elucidate the underlying mechanisms. In vivo, silibinin showed significant efficacy in inhibiting adiposity, improving lipid profile levels, ameliorating hepatic histological aberrations, healing the intestinal epithelium, and restoring gut microbiota compositions. Furthermore, in vitro, silibinin effectively inhibited FFA-induced lipid accumulation in HepG2 cells. Mechanistically, we reveal that silibinin possesses the ability to ameliorate hepatic lipotoxicity by suppressing the heat shock protein 90 (Hsp90)/peroxisome proliferator-activated receptor-γ (PPARγ) pathway and alleviating gut dysfunction by inhibiting the Hsp90/NOD-like receptor pyrin domain-containing 3 (NLRP3) pathway. Altogether, our findings provide evidence that silibinin is a promising candidate for alleviating the "multiple-hit" in the progression of NAFLD.

Poor Self-Reported Sleep is Associated with Prolonged White Matter T2 Relaxation in Psychotic Disorders.

Background: Schizophrenia (SZ) and bipolar disorder (BD) are characterized by white matter (WM) abnormalities, however, their relationship with illness presentation is not clear. Sleep disturbances are common in both disorders, and recent evidence suggests that sleep plays a critical role in WM physiology. Therefore, it is plausible that sleep disturbances are associated with impaired WM integrity in these disorders. To test this hypothesis, we examined the association of self-reported sleep disturbances with WM transverse (T2) relaxation times in patients with SZ spectrum disorders and BD with psychotic features. Methods: 28 patients with psychosis (17 BD-I, with psychotic features and 11 SZ spectrum disorders) were included. Metabolite and water T2 relaxation times were measured in the anterior corona radiata at 4T. Sleep was evaluated using the Pittsburgh Sleep Quality Index. Results: PSQI total score showed a moderate to strong positive correlation with water T2 (r = 0.64, p<0.001). Linear regressions showed that this association was specific to sleep disturbance but was not a byproduct of exacerbation in depressive, manic, or psychotic symptoms. In our exploratory analysis, sleep disturbance was correlated with free water percentage, suggesting that increased extracellular water may be a mechanism underlying the association of disturbed sleep and prolonged water T2 relaxation. Conclusion: Our results highlight the connection between poor sleep and WM abnormalities in psychotic disorders. Future research using objective sleep measures and neuroimaging techniques suitable to probe free water is needed to further our insight into this relationship.

Anti-tumor effects of telmisartan in glioma-astrocyte non-contact co-cultures: A critical role of astrocytic IL-6-mediated paracrine growth promotion.

Telmisartan, an angiotensin II type 1 receptor (AT1R) blocker, exhibits broad anti-tumor activity. However, in vitro, anti-proliferative effects are shown at doses far beyond the therapeutic plasma concentration. Considering the role of tumor microenvironment in glioma progression, glioma-astrocyte co-cultures were employed to test the anti-tumor potential of low-dose telmisartan. When a high dose was required for a direct anti-proliferative effect on glioma cell lines, a low dose significantly inhibited glioma cell proliferation and migration in the co-culture system. Under co-culture conditions, upregulated IL-6 expression in astrocytes played a critical role in glioma progression. Silencing IL-6 in astrocytes or IL-6R in glioma cells reduced proliferation and migration. Telmisartan (5 µM) inhibited astrocytic IL-6 expression, and its anti-tumor effects were reversed by silencing IL-6 or IL-6R and inhibiting signal transducer and activator of transcription 3 (STAT3) activity in glioma cells. Moreover, the telmisartan-driven IL-6 downregulation was not imitated by losartan, an AT1R blocker with little capacity of peroxisome proliferator-activated receptor-gamma (PPARγ) activation, but was eliminated by a PPARγ antagonist, indicating that the anti-glioma effects of telmisartan rely on its PPARγ agonistic activity rather than AT1R blockade. This study highlights the importance of astrocytic IL-6-mediated paracrine signaling in glioma growth and the potential of telmisartan as an adjuvant therapy for patients with glioma, especially those with hypertension.

CircCFL1 Promotes TNBC Stemness and Immunoescape via Deacetylation-Mediated c-Myc Deubiquitylation to Facilitate Mutant TP53 Transcription.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. TP53, which has a mutation rate of ≈70%-80% in TNBC patients, plays oncogenic roles when mutated. However, whether circRNAs can exert their effects on TNBC through regulating mutant TP53 has not been well evaluated. In this study, circCFL1, which is highly expressed in TNBC cells and tissues and has prognostic potential is identified. Functionally, circCFL1 promoted the proliferation, metastasis and stemness of TNBC cells. Mechanistically, circCFL1 acted as a scaffold to enhance the interaction between HDAC1 and c-Myc, further promoting the stability of c-Myc via deacetylation-mediated inhibition of K48-linked ubiquitylation. Stably expressed c-Myc further enhanced the expression of mutp53 in TNBC cells with TP53 mutations by directly binding to the promoter of TP53, which promoted the stemness of TNBC cells via activation of the p-AKT/WIP/YAP/TAZ pathway. Moreover, circCFL1 can facilitate the immune escape of TNBC cells by promoting the expression of PD-L1 and suppressing the antitumor immunity of CD8+ T cells. In conclusion, the results revealed that circCFL1 plays an oncogenic role by promoting the HDAC1/c-Myc/mutp53 axis, which can serve as a potential diagnostic biomarker and therapeutic target for TNBC patients with TP53 mutations.

Molecular and morphological evidence supports the resurrection of Chrysospleniumguangxiense H.G.Ye & Gui C.Zhang (Saxifragaceae).

Chrysospleniumguangxiense H.G.Ye & Gui C.Zhang was first described as a new species in 1994 but later synonymized in the Flora of China treatment with C.glossophyllum H.Hara. Plastid genomes and nrDNA sequences were used to infer the phylogenetic relationships of selected taxa in Chrysosplenium. Our phylogenetic analyses revealed that C.guangxiense belongs to sect. Alternifolia, is closely related to Chrysospleniumhydrocotylifolium H.Lév. & Vaniot but distant from C.glossophyllum. Morphologically, C.guangxiense could be easily distinguished from C.glossophyllum by having robust rhizomes, basal leaves with a long cuneate base and fewer teeth in the margin, curled sepal margins, and red, larger seeds. It could also be easily distinguished from C.hydrocotylifolium by possessing long elliptic leaves and a long cuneate leaf base. Along with the phylogenetic studies, the complete plastid genome of C.guangxiense was also reported. The plastid genome was 154,004 bp in length and comprised two inverted repeats (IRs) of 28,120 bp, separated by a large single-copy of 80,646 bp and a small single-copy of 17,118 bp. A total of 111 functional genes were discovered, comprising 78 protein-coding genes, 29 tRNA genes, and four rRNA genes. Based on assessment of morphological and molecular data Chrysospleniumguangxiense H.G.Ye & Gui C.Zhang is resurrected from C.glossophyllum H.Hara at species level. A global conservation assessment classifies C.guangxiense as Vulnerable (VU).

Metatranscriptomics-guided genome-scale metabolic reconstruction reveals the carbon flux and trophic interaction in methanogenic communities.

BACKGROUND: Despite rapid advances in genomic-resolved metagenomics and remarkable explosion of metagenome-assembled genomes (MAGs), the function of uncultivated anaerobic lineages and their interactions in carbon mineralization remain largely uncertain, which has profound implications in biotechnology and biogeochemistry. RESULTS: In this study, we combined long-read sequencing and metatranscriptomics-guided metabolic reconstruction to provide a genome-wide perspective of carbon mineralization flow from polymers to methane in an anaerobic bioreactor. Our results showed that incorporating long reads resulted in a substantial improvement in the quality of metagenomic assemblies, enabling the effective recovery of 132 high-quality genomes meeting stringent criteria of minimum information about a metagenome-assembled genome (MIMAG). In addition, hybrid assembly obtained 51% more prokaryotic genes in comparison to the short-read-only assembly. Metatranscriptomics-guided metabolic reconstruction unveiled the remarkable metabolic flexibility of several novel Bacteroidales-affiliated bacteria and populations from Mesotoga sp. in scavenging amino acids and sugars. In addition to recovering two circular genomes of previously known but fragmented syntrophic bacteria, two newly identified bacteria within Syntrophales were found to be highly engaged in fatty acid oxidation through syntrophic relationships with dominant methanogens Methanoregulaceae bin.74 and Methanothrix sp. bin.206. The activity of bin.206 preferring acetate as substrate exceeded that of bin.74 with increasing loading, reinforcing the substrate determinantal role. CONCLUSION: Overall, our study uncovered some key active anaerobic lineages and their metabolic functions in this complex anaerobic ecosystem, offering a framework for understanding carbon transformations in anaerobic digestion. These findings advance the understanding of metabolic activities and trophic interactions between anaerobic guilds, providing foundational insights into carbon flux within both engineered and natural ecosystems. Video Abstract.