H2O2 promotes photodynamic efficacy of TMPyP4 against ovarian cancer in vitro by downregulating HIF-1α expression.

Photodynamic therapy (PDT), employing photosensitizers to induce formation of reactive oxygen species (ROS) for tumor elimination, is emerging as a promising treatment modality in oncology due to its unique benefits. However, the PDT application in ovarian cancer, the most prevalent and lethal type of gynecological malignancy with a severe hypoxic microenvironment, remains unknown. This study revealed that photosensitizer TMPyP4 exhibited enhanced efficacy under H2O2 stimulation, with minimal change in cytotoxicity compared to TMPyP4 alone. The results showed that H2O2 increased ROS production induced by TMPyP4, leading to exacerbated mitochondrial dysfunction and DNA damage, ultimately inhibiting proliferation and inducing apoptosis in ovarian cancer cells. Mechanistically, H2O2 primarily enhanced the therapeutic efficacy of PDT with TMPyP4 against ovarian cancer cells by degrading HIF-1α, which subsequently modulated the HIF-1 signaling pathway, thereby alleviating the hypoxic environment in ovarian cancer cells. Our findings underscore the therapeutic potential of targeting HIF-1α within the hypoxic microenvironment for PDT in ovarian cancer and propose a novel integrated strategy for PDT treatment of this malignancy in vitro.

Synergistic role of phenylpropanoid biosynthesis and citrate cycle pathways in heavy metal detoxification through secretion of organic acids.

Excessive heavy metal contaminants in soils have serious ecological and environmental impacts, and affect plant growth and crop yields. Phytoremediation is an environmentally friendly means of lowering heavy metal concentrations in soils. In this study, we analyzed phenotypic and physiological traits, and the transcriptome and metabolome, of sheepgrass (Leymus chinensis) exposed to cadmium (Cd), lead (Pb), or zinc (Zn). Phenotypic and physiological analysis indicated that sheepgrass had strong tolerance to Cd/Pb/Zn. Transcriptomic analysis revealed that phenylpropanoid biosynthesis and organic acid metabolism were enriched among differentially expressed genes, and metabolomic analysis indicated that the citrate cycle was enriched in response to Cd/Pb/Zn exposure. Genes encoding enzymes involved in the phenylpropanoid and citrate cycle pathways were up-regulated under the Cd/Pb/Zn treatments. Organic acids significantly reduced heavy metal accumulation and improved sheepgrass tolerance of heavy metals. The results suggest that synergistic interaction of the phenylpropanoid and citrate cycle pathways in sheepgrass roots induced organic acid secretion to alleviate heavy metal toxicity. A cascade of enzymes involved in the interacting pathways could be targeted in molecular design breeding to enhance phytoremediation.

Association between dietary riboflavin intake and cognitive decline in older adults: a cross-sectional analysis.

BACKGROUND: Research exploring the link between dietary riboflavin intake and cognitive decline in this demographic is limited. Our aim was to examine the association between riboflavin intake levels and cognitive decline. METHODS: The National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2014 were utilized in this cross-sectional analysis. The Consortium to Establish a Registry for Alzheimer's Disease test Word Learning delayed recall trial (DR), Digit Symbol Substitution Test (DSST), Animal Fluency Test(AFT) and Z test were used to evaluate cognitive performance. Multivariate logistic regression, restricted cubic spline and subgroup analysis were performed to evaluate the associations between riboflavin intake and cognitive decline. RESULTS: The study included a total of 2255 patients, with 47.9% being male. The incidence of cognitive decline was 23.8%. After adjusting for all selected covariates, we found that high riboflavin intake was associated with a lower risk of cognitive impairment in adults in the United States. When riboflavin intake was used as a Categorical variable, compared to those with the lowest intake, the odds ratio (OR) of individuals with the highest riboflavin intake for DR test, AFT test, DSST test and Z test were 0.73 (95% CI: 0.53~1), 0.68(95% CI: 0.49-0.96),0.53(95% CI: 0.37-0.77) and 0.56(95% CI: 0.39-0.8). The study also found an L-shaped association between riboflavin intake and cognitive decline, with an inflection point at approximately 2.984 mg/d. CONCLUSIONS: Our cross-sectional study in a nationwide sample of American old adults suggests that dietary riboflavin intake was negative associated with cognitive decline.

Programmable Release of Chemotherapeutics from Ferrocene-Based Injectable Hydrogels Slows Melanoma Growth.

Hydrogel-based injectable drug delivery systems provide temporally and spatially controlled drug release with reduced adverse effects on healthy tissues. Therefore, they represent a promising therapeutic option for unresectable solid tumor entities. In this study, a peptide-starPEG/hyaluronic acid-based physical hydrogel is modified with ferrocene to provide a programmable drug release orchestrated by matrix-drug interaction and local reactive oxygen species (ROS). The injectable ROS-responsive hydrogel (hiROSponse) exhibits adequate biocompatibility and biodegradability, which are important for clinical applications. HiROSponse is loaded with the two cytostatic drugs (hiROSponsedox/ptx) doxorubicin (dox) and paclitaxel (ptx). Dox is a hydrophilic compound and its release is mainly controlled by Fickian diffusion, while the hydrophobic interactions between ptx and ferrocene can control its release and thus be regulated by the oxidation of ferrocene to the more hydrophilic state of ferrocenium. In a syngeneic malignant melanoma-bearing mouse model, hiROSponsedox/ptx slows tumor growth without causing adverse side effects and doubles the relative survival probability. Programmable release is further demonstrated in a tumor model with a low physiological ROS level, where dox release, low dose local irradiation, and the resulting ROS-triggered ptx release lead to tumor growth inhibition and increased survival.

Designing Organic Spin-Gapless Semiconductors via Molecular Adsorption on C4N3 Monolayer.

Spin-gapless semiconductor (SGS), a class of zero-gap materials with fully spin-polarized electrons and holes, offers significant potential for high-speed, low-energy consumption applications in spintronics, electronics, and optoelectronics. Our first-principles calculations revealed that the Pca21 C4N3 monolayer exhibits a ferromagnetic ground state. Its band structure displays SGS-like characteristics, with the energy gap between the valence and conduction bands near the Fermi level in the spin-down channel much smaller than the one in the other spin channel. To enhance its SGS properties, we introduced electrons into the Pca21 C4N3 monolayer by adsorbing the CO gas molecule on its surface. Stable gas adsorption (CO@C4N3) effectively narrowed the band gap in the spin-down channel without changing the band gap in the spin-up channel obviously. Moreover, injecting holes into the CO@C4N3 system could increase the net magnetic moments and induce an SGS-to-metallic phase transition, while injecting electrons into the CO@C4N3 system is able to lower the net magnetic moments and cause an SGS-to-half-metallic phase transition. Our findings not only underscore a new promising material for practical metal-free spintronics applications but also illustrate a viable pathway for designing SGSs.

Information propagation of focus wave mode localized waves in anisotropic turbulent seawater.

The evolution of the information transfer capability of an optical system for underwater focused wave mode localized wave (FWMLW) in anisotropic weakly turbulent absorbing seawater is studied. By developing the probability distribution function as well as the detection probability of the vortex modes carried by the FWMLW and the average bit error rate of the FWMLW underwater system, the information capacity of the FWMLW system with a pointing error is modeled. Through a numerical analysis of the effects of turbulent seawater and optical system parameters on the built light intensity, the detection probability, and the information capacity models, we find that the FWMLW system has an optimal delay time determined by the spectrum bandwidth when the spectrum bandwidth is greater than 1. The information capacity of the FWMLW system is higher than that of the X localized wave system under the same turbulent seawater channel condition, and FWMLW is a better optical signal source for vortex mode division multiplexing underwater systems than a Bessel-Gaussian beam.

Cell-specific models of hiPSC-CMs developed by the gradient-based parameter optimization method fitting two different action potential waveforms.

Parameter optimization (PO) methods to determine the ionic current composition of experimental cardiac action potential (AP) waveform have been developed using a computer model of cardiac membrane excitation. However, it was suggested that fitting a single AP record in the PO method was not always successful in providing a unique answer because of a shortage of information. We found that the PO method worked perfectly if the PO method was applied to a pair of a control AP and a model output AP in which a single ionic current out of six current species, such as IKr, ICaL, INa, IKs, IKur or IbNSC was partially blocked in silico. When the target was replaced by a pair of experimental control and IKr-blocked records of APs generated spontaneously in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), the simultaneous fitting of the two waveforms by the PO method was hampered to some extent by the irregular slow fluctuations in the Vm recording and/or sporadic alteration in AP configurations in the hiPSC-CMs. This technical problem was largely removed by selecting stable segments of the records for the PO method. Moreover, the PO method was made fail-proof by running iteratively in identifying the optimized parameter set to reconstruct both the control and the IKr-blocked AP waveforms. In the lead potential analysis, the quantitative ionic mechanisms deduced from the optimized parameter set were totally consistent with the qualitative view of ionic mechanisms of AP so far described in physiological literature.

Smart Microneedle Arrays Integrating Cell-Free Therapy and Nanocatalysis to Treat Liver Fibrosis.

Liver fibrosis is a chronic pathological condition lacking specific clinical treatments. Stem cells, with notable potential in regenerative medicine, offer promise in treating liver fibrosis. However, stem cell therapy is hindered by potential immunological rejection, carcinogenesis risk, efficacy variation, and high cost. Stem cell secretome-based cell-free therapy offers potential solutions to address these challenges, but it is limited by low delivery efficiency and rapid clearance. Herein, an innovative approach for in situ implantation of smart microneedle (MN) arrays enabling precisely controlled delivery of multiple therapeutic agents directly into fibrotic liver tissues is developed. By integrating cell-free and platinum-based nanocatalytic combination therapy, the MN arrays can deactivate hepatic stellate cells. Moreover, they promote excessive extracellular matrix degradation by more than 75%, approaching normal levels. Additionally, the smart MN arrays can provide hepatocyte protection while reducing inflammation levels by ≈70-90%. They can also exhibit remarkable capability in scavenging almost 100% of reactive oxygen species and alleviating hypoxia. Ultimately, this treatment strategy can effectively restrain fibrosis progression. The comprehensive in vitro and in vivo experiments, supplemented by proteome and transcriptome analyses, substantiate the effectiveness of the approach in treating liver fibrosis, holding immense promise for clinical applications.

Mechanistic insights into δ-MnO2/biochar-activated persulfate-treated wastewater containing antibiotics and heavy metals: Nonradical pathway and pivotal role of Cu(⠡) at low temperature.

Herein, we present a high efficiency system based on biochar loaded with layered manganese dioxide to remove tetracycline and heavy metals from livestock wastewater. Under the optimal conditions, the degradation efficiencies of TC in the δ-MnO2/BC/PS system were 85.5% at 25 °C and 38.5% at 5 °C. Radical quenching experiments revealed that radical reactions in the δ-MnO2/BC/PS system were weak under 15 °C. Adsorption degradation experiments showed that the system maintained good adsorption performance at 5 °C. Galvanic cell experiments and cyclic voltammetry showed that the δ-MnO2/BC material had good electrochemical activity and high stability in response to temperature, indicating that TC was degraded by a nonradical pathway that was not limited by temperature, such as electron transfer. Copper ion was important coadsorbent and coactivator of the reaction system. Furthermore, FTIR, XPS, and X-ray diffraction (XRD) analyses showed that Cu(II) in the system was involved in changing the manganese valence state in the δ-MnO2/BC material and increasing the -OH content of BC. Comparison of the different products generated during metabolic testing revealed that the reaction pathway of the system at low temperature (5 °C) differed from that at normal temperature (25 °C). The δ-MnO2/BC material demonstrated good removal ability for antibiotics and heavy metals at normal and low temperatures in actual biogas slurry. The study provides insight for improving the efficiency of environmentally friendly treatments of aquaculture wastewater in cold regions, which is of great significance for resource utilization.

Determinants of users' unverified information sharing on social media platforms: A herding behavior perspective.

The proliferation of unverified or false information by irresponsible users can significantly amplify the spread of misinformation or fake news. Despite growing research on unverified information sharing, a comprehensive understanding of the varying influences of different factors and strategies to mitigate this issue remains under investigation. To address this research gap, this study, rooted in the theory of herd behavior, develops, and tests a model theorizing the reasons behind social media users' unverified information sharing. Data was collected from 510 respondents across six regions of China using a convenience sampling method. The collected data was analyzed using Mplus. The results from this study indicated that perceived severity, state uncertainty, and herding have a significant positive influence on unverified information sharing. These results enrich the understanding of unverified information-sharing behavior among Chinese social media users. Drawing from these results, we suggest platform administrators and policymakers mitigate herd behavior tendencies and stem the spread of misinformation by disseminating timely, accurate, and authoritative information. Since this action will reduce users' perceptions of severity and uncertainty. Social media users are also advised to stay vigilant over the implications of herd behavior and foster a more critical attitude towards information sharing.

Predicting the potential deterioration of Barrett's esophagus based on gut microbiota: a Mendelian randomization analysis.

Esophageal adenocarcinoma (EAC) is one of the most malignant tumors in the digestive system. To make thing worse, the scarcity of treatment options is disheartening. However, if detected early, there is a possibility of reversing the condition. Unfortunately, there is still a lack of relevant early screening methods. Considering that Barrett's esophagus (BE), a precursor lesion of EAC, has been confirmed as the only known precursor of EAC. Analyzing which BE cases will progress to EAC and understanding the processes and mechanisms involved is of great significance for early screening of such patients. Considering the significant alterations in the gut microbiota of patients with BE and its potential role in the progression to EAC, this study aims to analyze the relationship between BE, EAC, and GM to identify potential diagnostic biomarkers and therapeutic targets. This study utilized comprehensive statistical data on gut microbiota from a large-scale genome-wide association meta-analysis conducted by the MiBioGen consortium (n = 18,340). Subsequently, we selected a set of single nucleotide polymorphisms (SNPs) that fell below the genome-wide significance threshold (1 × 10-5) as instrumental variables. To investigate the causal relationship between gut microbiota and BE and EAC, we employed various MR analysis methods, including Inverse Variance Weighting (IVW), MR-Egger regression, weighted median (WM), and weighted mean. Additionally, we assessed the level of pleiotropy, heterogeneity, and stability of genetic variations through MR-Egger intercept test, MR-PRESSO, Cochran's Q test, and "leave-one-out" sensitivity analysis. Furthermore, we conducted reverse MR analysis to identify the causal relationships between gut microbiota and BE and EAC. The results from the Inverse Variance-Weighted (IVW) analysis indicate that Alistipes (P = 4.86 × 10-2), Lactobacillus (P = 2.11 × 10-2), Prevotella 7 (P = 4.28 × 10-2), and RuminococcaceaeUCG004 (P = 4.34 × 10-2) are risk factors for Barrett's esophagus (BE), while Flavonifractor (P = 8.81 × 10-3) and RuminococcaceaeUCG004 (P = 4.99 × 10-2) are risk factors for esophageal adenocarcinoma (EAC). On the other hand, certain gut microbiota genera appear to have a protective effect against both BE and EAC. These include Eubacterium (nodatum group) (P = 4.51 × 10-2), Holdemania (P = 1.22 × 10-2), and Lactococcus (P = 3.39 × 10-2) in the BE cohort, as well as Eubacterium (hallii group) (P = 4.07 × 10-2) and Actinomyces (P = 3.62 × 10-3) in the EAC cohort. According to the results of reverse MR analysis, no significant causal effects of BE and EAC on gut microbiota were observed. Furthermore, no significant heterogeneity or pleiotropy was detected in the instrumental variables. We have established a causal relationship between the gut microbiota and BE and EAC. This study holds profound significance for screening BE patients who may be at risk of deterioration, as it can provide them with timely medical interventions to reverse the condition.

The binding effects and mechanisms of dissolved organic matter (DOM) on the fate of mercury in sludge anaerobic digestion combined with thermal hydrolysis.

Dissolved organic matter (DOM) plays an important role in regulating the fate of mercury (Hg), e.g., mobility, bioavailability, and toxicity. Clarifying the role of DOM in binding Hg in the treatment processes of sewage sludge is important for relieving Hg contamination risks in land applications. However, the impacts of DOM on Hg binding in sewage sludge are still unclear. In this study, we investigated the evolution of Hg and its speciation in full-scale sludge anaerobic digestion (AD) with thermal hydrolysis. The role of DOM in binding Hg(II) was further analyzed. The results showed that AD with thermal hydrolysis led to an increase in the Hg content in the sludge (from 3.72 ± 0.47 mg/kg to 10.75 ± 0.16 mg/kg) but a decrease in Hg mobility (the mercury sulfide fraction increased from 60.56 % to 79.78 %). Further adsorption experiments revealed that at equivalent DOM concentrations, DOM with a low molecular weight (MW<1 kDa) in activated sludge, DOM with a medium molecular weight (1 kDa 5 kDa) in both anaerobically digested sludge and conditioned sludge showed high binding amounts of Hg(II), with 1372.54, 535.28, 942.09 and 801.51 mg Hg/g DOM, respectively. Parallel factor analysis (PARAFAC) and fluorescence quotient (FQ) results showed that tryptophan-like and tyrosine-like substances had high binding affinities for Hg(II). Furthermore, X-ray photoelectron spectroscopy (XPS) indicated that the reduced organic sulfur contained in the DOM was potentially bound to Hg through the interactions of Hg-S and Hg-O. These results indicated that DOM may play special roles in regulating Hg speciation. The association between DOM and Hg(II), such as the significant positive correlation (p < 0.05) between the dissolution rate of Hg(II) and release of tryptophan-like substances during thermal hydrolysis, suggested the potential way for removing Hg from sludge.

High coverage of targeted lipidomics revealed lipid changes in the follicular fluid of patients with insulin-resistant polycystic ovary syndrome and a positive correlation between plasmalogens and oocyte quality.

Background: Polycystic ovary syndrome with insulin resistance (PCOS-IR) is the most common endocrine and metabolic disease in women of reproductive age, and low fertility in PCOS patients may be associated with oocyte quality; however, the molecular mechanism through which PCOS-IR affects oocyte quality remains unknown. Methods: A total of 22 women with PCOS-IR and 23 women without polycystic ovary syndrome (control) who underwent in vitro fertilization and embryo transfer were recruited, and clinical information pertaining to oocyte quality was analyzed. Lipid components of follicular fluid (FF) were detected using high-coverage targeted lipidomics, which identified 344 lipid species belonging to 19 lipid classes. The exact lipid species associated with oocyte quality were identified. Results: The number (rate) of two pronuclear (2PN) zygotes, the number (rate) of 2PN cleaved embryos, and the number of high-quality embryos were significantly lower in the PCOS-IR group. A total of 19 individual lipid classes and 344 lipid species were identified and quantified. The concentrations of the 19 lipid species in the normal follicular fluid (control) ranged between 10-3 mol/L and 10-9 mol/L. In addition, 39 lipid species were significantly reduced in the PCOS-IR group, among which plasmalogens were positively correlated with oocyte quality. Conclusions: This study measured the levels of various lipids in follicular fluid, identified a significantly altered lipid profile in the FF of PCOS-IR patients, and established a correlation between poor oocyte quality and plasmalogens in PCOS-IR patients. These findings have contributed to the development of plasmalogen replacement therapy to enhance oocyte quality and have improved culture medium formulations for oocyte in vitro maturation (IVM).

Cyclosporin A-Based PROTACs Can Deplete Abundant Cellular Cyclophilin A without Suppressing T Cell Activation.

Cyclophilin A (CypA), the cellular receptor of the immunosuppressant cyclosporin A (CsA), is an abundant cytosolic protein and is involved in a variety of diseases. For example, CypA supports cancer proliferation and mediates viral infections, such as the human immunodeficiency virus 1 (HIV-1). Here, we present the design of PROTAC (proteolysis targeting chimera) compounds against CypA to induce its intracellular proteolysis and to investigate their effect on immune cells. Interestingly, upon connecting to E3 ligase ligands, both peptide-based low-affinity binders and CsA-based high-affinity binders can degrade CypA at nM concentration in HeLa cells and fibroblast cells. As the immunosuppressive effect of CsA is not directly associated with the binding of CsA to CypA but the inhibition of phosphatase calcineurin by the CypA:CsA complex, we investigated whether a CsA-based PROTAC compound could induce CypA degradation without affecting the activation of immune cells. P3, the most efficient PROTAC compound discovered from this study, could deplete CypA in lymphocytes without affecting cell proliferation and cytokine production. This work demonstrates the feasibility of the PROTAC approach in depleting the abundant cellular protein CypA at low drug dosage without affecting immune cells, allowing us to investigate the potential therapeutic effects associated with the endogenous protein in the future.

RAPSYN-mediated neddylation of BCR-ABL alternatively determines the fate of Philadelphia chromosome-positive leukemia.

Philadelphia chromosome-positive (Ph+) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph+ leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph+ leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph+ leukemia.

Chronic myeloid leukemia (CML for short) accounts for about 15% of all blood cancers diagnosed in adults in the United States. The condition is characterized by the overproduction of immature immune cells that interfere with proper blood function. It is linked to a gene recombination (a type of mutation) that leads to white blood cells producing an abnormal 'BCR-ABL' enzyme which is always switched on. In turn, this overactive protein causes the cells to live longer and divide uncontrollably. Some of the most effective drugs available to control the disease today work by blocking the activity of BCR-ABL. Yet certain patients can become resistant to these treatments over time, causing them to relapse. Other approaches are therefore needed to manage this disease; in particular, a promising avenue of research consists in exploring whether it is possible to reduce the amount of the enzyme present in diseased cells. As part of this effort, Zhao, Dai, Li, Zhang et al. focused on RAPSYN, a scaffolding protein previously unknown in CML cells. In other tissues, it has recently been shown to participate in neddylation ­ a process by which proteins receive certain chemical 'tags' that change the way they behave. The experiments revealed that, compared to healthy volunteers, RAPSYN was present at much higher levels in the white blood cells of CML patients. Experimentally lowering the amount of RAPSYN in CML cells led these to divide less quickly ­ both in a dish and when injected in mice, while also being linked to decreased levels of BCR-ABL. Additional biochemical experiments indicated that RAPSYN sticks with BCR-ABL to add chemical 'tags' that protect the abnormal protein against degradation, therefore increasing its overall levels. Finally, the team showed that SRC, an enzyme often dysregulated in emerging cancers, can activate RAPSYN's ability to conduct neddylation; such mechanism could promote BCR-ABL stabilization and, in turn, disease progression. Taken together, these experiments indicate a new way by which BCR-ABL levels are controlled. Future studies should investigate whether RAPSYN also stabilizes BCR-ABL in patients whose leukemias have become resistant to existing drugs. Eventually, RAPSYN may offer a new target for overcoming drug-resistance in CML patients.

High-Refractive-Index Cross-Linked Cyclic Olefin Polymers with Excellent Transparency via Thiol-Ene Click Reaction.

High-refractive-index polymers are important optical materials in optoelectronics. Conventional cyclic olefin polymers (COPs), possessing many excellent optical properties, are a class of highly promising optical materials; however, one of the greatest obstacles is their low refractive index of n = 1.52-1.54. Here, one efficient strategy of first incorporating high molar refraction groups, including carbazolyl and indolyl moieties, into unsaturated COPs via ring-opening metathesis polymerization (ROMP) and then introducing another high molar refraction sulfur atom by a subsequent thiol-ene click reaction is presented. The obtained cross-linked COPs bearing both an aromatic group and sulfur possess significantly higher refractive indices (n = 1.611-1.684 at 589 nm) and highly optical transparency (approximately 95%) in the range of vis-NIR. This provides a way toward potential applications of new-generation optical materials.

Injectable alginate-based zwitterionic hydrogels promoting endometrial repair and restoring fertility.

The development of novel therapeutic approaches to facilitate endometrial repair and regeneration while preventing adhesion recurrence is a crucial research objective aimed at enhancing clinical outcomes for women with intrauterine adhesions (IUA). In this study, we introduced an injectable Alg-GMA/PTSB zwitterionic hydrogel, characterized by excellent biocompatibility, anti-protein adsorption properties, and biodegradability. In a rat model, the hydrogel significantly promoted the regeneration and angiogenesis of damaged endometrial tissue, leading to improved recovery of epithelial cells, glands, proliferation, and vascularization. Furthermore, it exhibited the ability to suppress cellular apoptosis and collagen deposition, thereby mitigating fibrosis. Additionally, the hydrogel restored the expression of estrogen/progesterone receptors and endometrial receptivity markers, contributing to enhanced embryo implantation and fertility. These findings underscore the potential of the hydrogel as a promising therapeutic strategy for addressing endometrial injury, reducing fibrosis, restoring fertility, and ultimately improving outcomes for women with IUA.

Nociceptive adenosine A2A receptor on trigeminal nerves orchestrates CGRP release to regulate the progression of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) associated pain commonly predicts adverse events among patients. This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy. However, it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression. In this study, we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo, as evidenced by clinical tissue microarray analysis and murine lingual denervation. We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort. Notably, such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A2A receptor (A2AR) on trigeminal ganglia. Antagonism of trigeminal A2AR with a selective A2AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo. We showed that trigeminal A2AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP, an effect counteracted by SCH58261. We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP. Finally, we diminished the impact of CGRP on OSCC with istradefylline, a clinically available drug that targets neuronal A2AR. Therefore, we established trigeminal A2AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.

Curcumin alleviates Aflatoxin B1-triggered chicken liver necroptosis by targeting the LOC769044/miR-1679/STAT1 axis.

Aflatoxin B1 (AFB1) is an unavoidable environmental toxin. The accumulation of AFB1 and its metabolites in the liver poses a threat to both human and animal health. Curcumin exhibits anti-oxidative, anti-tumor, and anti-inflammatory properties. There is no report on the mechanism regarding how curcumin relived liver necroptosis in chickens induced by AFB1 based on the regulatory network of ceRNA. To explore this, we performed transmission electron microscopy and sequenced lncRNA and mRNA in chicken livers treated with AFB1 and/or curcumin for 28 d in vivo. We observed substantial alterations in the lncRNA and mRNA expression profiles within the chicken liver, indicating that curcumin can mitigate AFB1-induced necroptosis both in vivo and in vitro. Further analysis, including the establishment of an lncRNA-miRNA-mRNA network and the utilization of a dual luciferase reporter assay, revealed that LOC769044 acts as a competing endogenous RNA (ceRNA) for miR-1679. In addition, STAT1 was identified as a direct target of miR-1679. Modulating miR-1679 levels through overexpression, and silencing LOC769044 and STAT1, effectively reversed the necroptotic effects induced by AFB1, a reversal that was also observed with curcumin supplementation. In conclusion, our data demonstrate that curcumin alleviates AFB1-induced liver necroptosis through the LOC769044/miR-1679/STAT1 signaling axis. This study suggests that LOC769044 may serve as a novel therapeutic target for managing AFB1-mediated liver toxicity.