The combined toxicity of polystyrene nano/micro-plastics and triphenyl phosphate (TPHP) on HepG2 cells.

Combined toxicity is a critical concern during the risk assessment of environmental pollutants. Due to the characteristics of strong hydrophobicity and large specific surface area, microplastics (MPs) and nanoplastics (NPs) have become potential carriers of organic pollutants that may pose a health risk to humans. The co-occurrence of organic pollutants and MPs would cause adverse effects on aquatic organism, while the information about combined toxicity induced by organophosphorus flame retardants and MPs on human cells was limited. This study aimed to reveal the toxicity effects of co-exposure to triphenyl phosphate (TPHP) and polystyrene (PS) particles with micron-size/nano-size on HepG2 cell line. The adsorption behaviors of TPHP on PS particles was observed, with the PS-NP exhibiting a higher adsorption capacity. The reactive oxygen species generation, mitochondrial membrane potential depolarization, lactate dehydrogenase release and cell apoptosis proved that PS-NPs/MPs exacerbated TPHP-induced cytotoxicity. The particle size of PS would affect the toxicity to HepG2 cells that PS-NP (0.07 µm) exhibited more pronounced combined toxicity than PS-MP (1 µm) with equivalent concentrations of TPHP. This study provides fundamental insights into the co-toxicity of TPHP and PS micro/nanoplastics in HepG2 cells, which is crucial for validating the potential risk of combined toxicity in humans.

Recent research on material-based methods for isolation of extracellular vesicles.

Extracellular vesicles (EVs) are nanoparticles secreted by cells with a closed phospholipid bilayer structure, which can participate in various physiological and pathological processes and have significant clinical value in disease diagnosis, targeted therapy and prognosis assessment. EV isolation methods currently include differential ultracentrifugation, ultrafiltration, size exclusion chromatography, immunoaffinity, polymer co-precipitation and microfluidics. In addition, material-based biochemical or biophysical approaches relying on intrinsic properties of the material or its surface-modified functionalized monomers, demonstrated unique advantages in the efficient isolation of EVs. In order to provide new ideas for the subsequent development of material-based EV isolation methods, this review will focus on the principle, research status and application prospects of material-based EV isolation methods based on different material carriers and functional monomers.

Kanglexin counters vascular smooth muscle cell dedifferentiation and associated arteriosclerosis through inhibiting PDGFR.

BACKGROUND: Dysregulation of vascular smooth muscle cell (VSMC) function leads to a variety of diseases such as atherosclerosis and hyperplasia after injury. However, antiproliferative drug targeting VSMC exhibits poor specificity. Therefore, there is an urgent to develop highly specific antiproliferative drugs to prevention and treatment VSMC dedifferentiation associated arteriosclerosis. Kanglexin (KLX), a new anthraquinone compound designed by our team, has potential to regulate VSMC phenotype according to the physicochemical properties. PURPOSE: This project aims to evaluate the therapeutic role of KLX in VSMC dedifferentiation and atherosclerosis, neointimal formation and illustrates the underlying molecular mechanism. METHODS: In vivo, the ApoE-/- mice were fed with high-fat diet (HFD) for a duration of 13 weeks to establish the atherosclerotic model. And rat carotid artery injury model was performed to establish the neointimal formation model. In vitro, PDGF-BB was used to induce VSMC dedifferentiation. RESULTS: We found that KLX ameliorated the atherosclerotic progression including atherosclerotic lesion formation, lipid deposition and collagen deposition in aorta and aortic sinus in atherosclerotic mouse model. In addition, The administration of KLX effectively ameliorated neointimal formation in the carotid artery following balloon injury in SD rats. The findings derived from molecular docking and surface plasmon resonance (SPR) experiments unequivocally demonstrate that KLX had potential to bind PDGFR-ß. Mechanism research work proved that KLX prevented VSMC proliferation, migration and dedifferentiation via activating the PDGFR-ß-MEK -ERK-ELK-1/KLF4 signaling pathway. CONCLUSION: Collectively, we demonstrated that KLX effectively attenuated the progression of atherosclerosis in ApoE-/- mice and carotid arterial neointimal formation in SD rats by inhibiting VSMC phenotypic conversion via PDGFR-ß-MEK-ERK-ELK-1/KLF4 signaling. KLX exhibits promising potential as a viable therapeutic agent for the treatment of VSMC phenotype conversion associated arteriosclerosis.

RAF1 facilitates KIT signaling and serves as a potential treatment target for gastrointestinal stromal tumor.

The aberrant activation of RAS/RAF/MEK/ERK signaling is important for KIT mutation-mediated tumorigenesis of gastrointestinal stromal tumor (GIST). In this study, we found that inhibition of RAF1 suppresses the activation of both wild-type KIT and primary KIT mutations in GIST, with primary KIT mutations showing greater sensitivity. This suggests a positive feedback loop between KIT and RAF1, wherein RAF1 facilitates KIT signaling. We further demonstrated that RAF1 associates with KIT and the kinase activity of RAF1 is necessary for its contribution to KIT activation. Accordingly, inhibition of RAF1 suppressed cell survival, proliferation, and cell cycle progression in vitro mediated by both wild-type KIT and primary KIT mutations. Inhibition of RAF1 in vivo suppressed GIST growth in a transgenic mouse model carrying germline KIT/V558A mutation, showing a similar treatment efficiency as imatinib, the first-line targeted therapeutic drug of GIST, while the combination use of imatinib and RAF1 inhibitor further suppressed tumor growth. Acquisition of drug-resistant secondary mutation of KIT is a major cause of treatment failure of GIST following targeted therapy. Like wild-type KIT and primary KIT mutations, inhibition of RAF1 suppressed the activation of secondary KIT mutation, and the cell survival, proliferation, cell cycle progression in vitro, and tumor growth in vivo mediated by secondary KIT mutation. However, the activation of secondary KIT mutation is less dependent on RAF1 compared with that of primary KIT mutations. Taken together, our results revealed that RAF1 facilitates KIT signaling and KIT mutation-mediated tumorigenesis of GIST, providing a rationale for further investigation into the use of RAF1 inhibitors alone or in combination with KIT inhibitor in the treatment of GIST, particularly in cases resistant to KIT inhibitors.

HDAC6-dependent deacetylation of NGF dictates its ubiquitination and maintains primordial follicle dormancy.

Rationale: Primordial follicles are limited in number and cannot be regenerated, dormant primordial follicles cannot be reversed once they enter a growth state. Therefore, the length of the female reproductive lifespan depends on the orderly progression and selective activation of primordial follicles, the mechanism of which remains unclear. Methods: We used human ovarian cortical biopsy specimens, granulosa cells from diminished ovarian reserve (DOR) patients, Hdac6-overexpressing transgenic mouse model, and RNA sequencing to analyze the crucial roles of histone deacetylase 6 (HDAC6) in fertility preservation and primordial follicle activation. Results: In the present study, we found that HDAC6 was highly expressed in most dormant primordial follicles. The HDAC6 expression was reduced accompanying reproductive senescence in human and mouse ovaries. Overexpression of Hdac6 delayed the rate of primordial follicle activation, thereby prolonging the mouse reproductive lifespan. Short-term inhibition of HDAC6 promoted primordial follicle activation and follicular development in humans and mice. Mechanism studies revealed that HDAC6 directly interacted with NGF, reducing acetylation modification of NGF and thereby accelerating its ubiquitination degradation. Consequently, the reduced NGF protein level maintained the dormancy of primordial follicles. Conclusions: The physiological significance of the high expression of HDAC6 in most primordial follicles is to reduce NGF expression and prevent primordial follicle activation to maintain female fertility. Reduced HDAC6 expression increases NGF expression in primordial follicles, activating their development and contributing to reproduction. Our study provides a clinical reference value for fertility preservation.

A facile cellulose finishing strategy through in-situ growth of sliver-doped manganese dioxide assisted by amine-quinone for improving indoor living quality.

Nowadays, various harmful indoor pollutants especially including bacteria and residual formaldehyde (HCHO) seriously threaten human health and reduce the quality of public life. Herein, a universal substrate-independence finishing approach for efficiently solving these hybrid indoor threats is demonstrated, in which amine-quinone network (AQN) was employed as reduction agent to guide in-situ growth of Ag@MnO2 particles, and also acted as an adhesion interlayer to firmly anchor nanoparticles onto diverse textiles, especially for cotton fabrics. In contrast with traditional hydrothermal or calcine methods, the highly reactive AQN ensures the efficient generation of functional nanoparticles under mild conditions without any additional catalysts. During the AQN-guided reduction, the doping of Ag atoms onto cellulose fiber surface optimized the crystallinity and oxygen vacancy of MnO2, providing cotton efficient antibacterial efficiency over 90 % after 30 min of contact, companying with encouraging UV-shielding and indoor HCHO purification properties. Besides, even after 30 cycles of standard washing, the Ag@MnO2-decorated textiles can effectively degrade HCHO while well-maintaining their inherent properties. In summary, the presented AQN-mediated strategy of efficiently guiding the deposition of functional particles on fibers has broad application prospects in the green and sustainable functionalization of textiles.

Four and a half LIM domains 2 (FHL2) attenuates tumorigenesis of gastrointestinal stromal tumors (GISTs) by negatively regulating KIT signaling.

Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild-type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild-type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first-line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild-type KIT and primary KIT mutants, we further found that FHL2 didn't alter the expression and activation of drug-resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.

Individualized prevention of proton pump inhibitor related adverse events by risk stratification.

Proton pump inhibitors (PPIs) are commonly used for gastric acid-related disorders, but their safety profile and risk stratification for high-burden diseases need further investigation. Analyzing over 2 million participants from five prospective cohorts from the US, the UK, and China, we found that PPI use correlated with increased risk of 15 leading global diseases, such as ischemic heart disease, diabetes, respiratory infections, and chronic kidney disease. These associations showed dose-response relationships and consistency across different PPI types. PPI-related absolute risks increased with baseline risks, with approximately 82% of cases occurring in those at the upper 40% of the baseline predicted risk, and only 11.5% of cases occurring in individuals at the lower 50% of the baseline risk. While statistical association does not necessarily imply causation, its potential safety concerns suggest that personalized use of PPIs through risk stratification might guide appropriate decision-making for patients, clinicians, and the public.

WSB1/2 target chromatin-bound lysine-methylated RelA for proteasomal degradation and NF-κB termination.

Proteasome-mediated degradation of chromatin-bound NF-κB is critical in terminating the transcription of pro-inflammatory genes and can be triggered by Set9-mediated lysine methylation of the RelA subunit. However, the E3 ligase targeting methylated RelA remains unknown. Here, we find that two structurally similar substrate-recognizing components of Cullin-RING E3 ligases, WSB1 and WSB2, can recognize chromatin-bound methylated RelA for polyubiquitination and proteasomal degradation. We showed that WSB1/2 negatively regulated a subset of NF-κB target genes via associating with chromatin where they targeted methylated RelA for ubiquitination, facilitating the termination of NF-κB-dependent transcription. WSB1/2 specifically interacted with methylated lysines (K) 314 and 315 of RelA via their N-terminal WD-40 repeat (WDR) domains, thereby promoting ubiquitination of RelA. Computational modeling further revealed that a conserved aspartic acid (D) at position 158 within the WDR domain of WSB2 coordinates K314/K315 of RelA, with a higher affinity when either of the lysines is methylated. Mutation of D158 abolished WSB2's ability to bind to and promote ubiquitination of methylated RelA. Together, our study identifies a novel function and the underlying mechanism for WSB1/2 in degrading chromatin-bound methylated RelA and preventing sustained NF-κB activation, providing potential new targets for therapeutic intervention of NF-κB-mediated inflammatory diseases.

A novel modified polydopamine based on melanin-like materials for antibacterial, hydrophobic, and ultraviolet protective of textiles.

The development of environmentally friendly multifunctional auxiliaries for textile modification is the focus of attention in textile industry in recent years. Polydopamine is an important biological macromolecule and widely used in biomedicine, nanomaterials, material surface modification and other fields. In this study, the novel multifunctional melanin-like nanoparticles (Nha-PDA NPs) were prepared and used for antibacterial, hydrophobic, and UV protective of textiles. Nha-PDA NPs were prepared with dopamine (DA) and n-hexylamine (Nha) by simple autoxidation copolymerization. Nha-PDA NPs were bound to the fabric surface through the PDA structure in Nha-PDA NPs that has been widely confirmed to have strong adhesion on the surface of many materials. The modified fabrics, Nha-PDA NPs@Cotton, had good hydrophobic, antibacterial and UV protective properties. The static water contact angles of the modified fabrics could reach 120°. The antibacterial rates of Nha-PDA NPs@Cotton against E. coli and S. aureus were above 85 %. The maximum UPF value of the modified cotton was 362, indicating that the ultraviolet protection performance was excellent. The fabric modified with multifunctional melanin-like nanoparticle provides a green way for the multifunctional modification of textiles.

Platycodin D facilitates antiviral immunity through inhibiting cytokine storm via targeting K63-linked TRAF6 ubiquitination.

Influenza virus infection is a worldwide challenge that causes heavy burdens on public health. The mortality rate of severe influenza patients is often associated with hyperactive immunological abnormalities characterized by hypercytokinemia. Due to the continuous mutations and the occurrence of drug-resistant influenza virus strains, the development of host-directed immunoregulatory drugs is urgently required. Platycodon grandiflorum is among the top 10 herbs of traditional Chinese medicine used to treat pulmonary diseases. As one of the major terpenoid saponins extracted from Platycodon grandiflorum, Platycodin D (PD) has been reported to play several roles, including anti-inflammation, analgesia, anti-cancer, hepatoprotection, and immunoregulation. However, the therapeutic roles of PD to treat influenza virus infection remains unknown. Here, we show that PD can protect the body weight loss in severely infected influenza mice, alleviate lung damage, and thus improve the survival rate. More specifically, PD protects flu mice via decreasing the immune cell infiltration into lungs and downregulating the overactivated inflammatory response. Western blot and immunofluorescence assays exhibited that PD could inhibit the activation of TAK1/IKK/NF-κB and MAPK pathways. Besides that, CETSA, SPR and immunoprecipitation assays indicated that PD binds with TRAF6 to decrease its K63 ubiquitination after R837 stimulation. Additionally, siRNA interference experiments exhibited that PD could inhibit the secretion of IL-1ß and TNF-α in TRAF6-dependent manner. Altogether, our results suggested that PD is a promising drug candidate for treating influenza. Our study also offered a scientific explanation for the commonly used Platycodon grandiflorum in many anti-epidemic classic formulas. Due to its host-directed regulatory role, PD may serve as an adjuvant therapeutic drug in conjunction with other antiviral drugs to treat the flu.

Simultaneous Visualization and Depletion of Peroxynitrite by a Simple Aggregation-Induced Emission Nanoprobe for Preventing Breast Cancer Metastasis after Surgery.

Inflammation has been confirmed to be closely related to the development of tumors, while peroxynitrite (ONOO-) is one of the most powerful oxidative pro-inflammatory factors. Although ONOO- can kill bacteria through oxidation, it will activate matrix metalloproteinases (MMPs), accelerate the degradation of the extracellular matrix (ECM), and subsequently lead to the activation and release of other tumor promotion factors existing in the ECM, promoting tumor metastasis and invasion. Herein, we report a simple aggregation-induced emission (AIE) nanoprobe (NP), TPE-4NMB, that can simultaneously visualize and deplete ONOO-. The probe can light up the endogenous and exogenous ONOO- in cells and selectively inhibit the proliferation and migration of 4T1 cells by inducing an intracellular redox homeostasis imbalance through ONOO- depletion. After being modified with DSPE-PEG2000, the TPE-4NMB NPs can be used to image ONOO- induced by various models in vivo; especially, it can monitor the dynamic changes of ONOO- level in the residual tumor after surgery, which can provide evidence for clarifying the association between surgery, ONOO-, and cancer metastasis. Excitingly, inhibited tumor volume growth and decreased counts of lung metastases were observed in the TPE-4NMB NPs group, which can be attributed to the downregulated expression of MMP-9 and transforming growth factor-ß (TGF-ß), increased cell apoptosis, and inhibited epithelial-mesenchymal transition (EMT) mediated by ONOO-. The results will provide new evidence for clarifying the relationship between surgery, ONOO-, and tumor metastasis and serve as a new intervention strategy for preventing tumor metastasis after tumor resection.

Photothermal, superhydrophobic, conductive, and anti-UV cotton fabric loaded with polydimethylsiloxane-encapsulated copper sulfide nanoflowers.

Multifunctional textiles have attracted widespread attention with the improvement of awareness of health. Especially, the fluorine-free superhydrophobic and conductive cellulose fiber-based fabrics have received intensive interest due to their broad and high-value applications. Herein, the copper sulfide nanoflowers were in-situ deposited on cotton fabric followed by polydimethylsiloxane (PDMS) treatment for encapsulating CuS nanoflowers and obtaining superhydrophobicity, recorded as Cot@PTA@CuS@PDMS. Cot@PTA@CuS@PDMS possesses superhydrophobicity with contact angles of 153.0 ± 0.4°, photothermal effect, excellent UV resistance, good conductivity, and anti-fouling. Interestingly, the resistance of Cot@PTA@CuS@PDMS is significantly reduced from 856.4 to 393.1 Ω under simulated sunlight irradiation with 250 mW/cm2. Notably, the resistance can be slightly recovered after shutting off simulated sunlight. Besides, Cot@PTA@CuS@PDMS has efficient oil-water separation efficiency for corn germ oil and castor oil, respectively. Briefly, this work provides a novel, facile, and promising strategy to fabricate multifunctional fiber-based textiles with the reversible change of resistance under simulated sunlight irradiation, inspiring more scholars to control the resistance change of textiles by light irradiation.

Zn2SnO4@Ti ceramic film anode preparation by microarc oxidation for 2e- WOR degradation of unsymmetrical dimethylhydrazine (UDMH).

The main challenge facing the anodic electro-Fenton through the 2e- water oxidation reaction (WOR) for toxics degradation lies in the electrode's stability, because the anodic oxygen evolution (OER) generated O2 will inevitably exfoliate the electro-active components loaded on the electrode substrate. To address this point, two aspects need attention: 1) Identifying a catalyst that exhibits both excellent electrocatalytic activity and selectivity can improve the faradaic efficiency of hydrogen peroxide (H2O2); 2) Employing novel methods for fabricating highly stable electrodes, where active sites can be firmly coated. Consequently, this study utilized microarc oxidation (MAO) to prepare a ceramic film electrode Zn2SnO4@Ti at 300 V. Zn2SnO4 acts as an WOR electrocatalyst and further improved the generation of H2O2 for treating real wastewater containing Unsymmetrical Dimethylhydrazine (UDMH). From the perspective of characterization of electrode structure, Zn2SnO4@Ti forms a stable active coating, the electrochemical yield of H2O2 is high up to 78.4 µmol h-1 cm-2, and the selectivity of H2O2 is over 80% at 3.3 V vs. RHE, which can be fully applied to scenarios where it is inconvenient to transport H2O2 and need in-situ safe production. Additionally, the prepared electrodes exhibit significant stability, suitable for various applications, providing insightful preparation strategies and experiences for constructing highly stable anodes.

Pan-genome analysis of Streptococcus suis serotype 2 highlights genes associated with virulence and antibiotic resistance.

Streptococcus suis serotype 2 (SS2) is a Gram-positive bacterium. It is a common and significant pathogen in pigs and a common cause of zoonotic meningitis in humans. It can lead to sepsis, endocarditis, arthritis, and pneumonia. If not diagnosed and treated promptly, it has a high mortality rate. The pan-genome of SS2 is open, and with an increasing number of genes, the core genome and accessory genome may exhibit more pronounced differences. Due to the diversity of SS2, the genes related to its virulence and resistance are still unclear. In this study, a strain of SS2 was isolated from a pig farm in Sichuan Province, China, and subjected to whole-genome sequencing and characterization. Subsequently, we conducted a Pan-Genome-Wide Association Study (Pan-GWAS) on 230 strains of SS2. Our analysis indicates that the core genome is composed of 1,458 genes related to the basic life processes of the bacterium. The accessory genome, consisting of 4,337 genes, is highly variable and a major contributor to the genetic diversity of SS2. Furthermore, we identified important virulence and resistance genes in SS2 through pan-GWAS. The virulence genes of SS2 are mainly associated with bacterial adhesion. In addition, resistance genes in the core genome may confer natural resistance of SS2 to fluoroquinolone and glycopeptide antibiotics. This study lays the foundation for further research on the virulence and resistance of SS2, providing potential new drug and vaccine targets against SS2.

Unique quinoline orientations shape the modified aptamer to sclerostin for enhanced binding affinity and bone anabolic potential.

Osteogenesis imperfecta (OI) is a rare genetic disease characterized by bone fragility and bone formation. Sclerostin could negatively regulate bone formation by antagonizing the Wnt signal pathway, whereas it imposes severe cardiac ischemic events in clinic. Our team has screened an aptamer that could promote bone anabolic potential without cardiovascular risk. However, the affinity of the aptamer is lower and needs to be improved. In the study, hydrophobic quinoline molecule with unique orientations (seven subtypes) were incorporated into key sites of a bone anabolic aptamer against sclerostin to form a modified aptamer library. Among all the quinoline modifications, 5-quinoline modification could shape the molecular recognition of modified aptamers to sclerostin to facilitate enhancing its binding to sclerostin toward the highest affinity by interacting with newly participated binding sites in sclerostin. Further, 5-quinoline modification could facilitate the modified aptamer attenuating the suppressed effect of the transfected sclerostin on both Wnt signaling and bone formation marker expression levels in vitro, promoting bone anabolism in OI mice (Col1a2+/G610C). The proposed quinoline-oriented modification strategy could shape the molecular recognition of modified aptamers to proteins to facilitate enhancing its binding affinity and therapeutic potency.

Disulfide bond network crosslinked flexible multifunctional chitosan coating on fabric surface prepared by the chitosan grafted with thioctic acid.

In this study, we propose a novel approach to improve the performance of chitosan coating, and thioctic acid with disulfide bonds in its molecular structure was grafted onto the side groups of chitosan macromolecules. The introduction of disulfide bond network cross-linking structure in chitosan coating weakens hydrogen bonds between chitosan macromolecules, causing the macromolecular chains to be more prone to relative motion when subjected to external forces, ultimately improving flexibility of the coating. The modified chitosan becomes more suitable for antibacterial modification in smart wearable fabrics. Subsequently, we fabricated a smart wearable fabric with excellent antibacterial properties and strong electromagnetic shielding by employing the layer-by-layer spraying technique. This involved incorporating chitosan with disulfide bonds and MXene nanoparticles. The fabric surfaces containing chitosan with disulfide bonds exhibited enhanced flexibility compared to unmodified chitosan fabric, resulting in an 8-point improvement in tactile sensation ratings. This research presents a novel approach that simultaneously enhances the electromagnetic shielding effectiveness and efficient antibacterial properties of smart wearable textiles. Consequently, it advances the application of chitosan in the field of antibacterial finishing for functional textiles.

Transformation process and phytotoxicity of sulfamethoxazole and N4-acetyl-sulfamethoxazole in rice.

Sulfonamide antibiotics, extensively used in human and veterinary therapy, accumulate in agroecosystem soils through livestock manure and sewage irrigation. However, the interaction between sulfonamides and rice plants remains unclear. This study investigated the transformation behavior and toxicity of sulfamethoxazole (SMX) and its main metabolite, N4-acetyl-sulfamethoxazole (NASMX) in rice. SMX and NASMX were rapidly taken up by roots and translocated acropetally. NASMX showed higher accumulating capacity, with NASMX concentrations up to 20.36 ± 1.98 µg/g (roots) and 5.62 ± 1.17 µg/g (shoots), and with SMX concentrations up to 15.97 ± 2.53 µg/g (roots) and 3.22 ± 0.789 µg/g (shoots). A total of 18 intermediate transformation products of SMX were identified by nontarget screening using Orbitrap-HRMS, revealing pathways such as deamination, hydroxylation, acetylation, formylation, and glycosylation. Notably, NASMX transformed back into SMX in rice, a novel finding. Transcriptomic analysis highlights the involvements of cytochrome P450 (CYP450), acetyltransferase (ACEs) and glycosyltransferases (GTs) in these biotransformation pathways. Moreover, exposure to SMX and NASMX disrupts TCA cycle, amino acid, linoleic acid, nucleotide metabolism, and phenylpropanoid biosynthesis pathways of rice, with NASMX exerting a stronger impact on metabolic networks. These findings elucidate the sulfonamides' metabolism, phytotoxicity mechanisms, and contribute to assessing food safety and human exposure risk amid antibiotic pollution.

Heraclenin promotes the osteogenic differentiation of bone marrow stromal cells by activating the RhoA/ROCK pathway.

BACKGROUND: Osteoporosis is a devastating skeletal disease, the pathogenesis of which is related to abnormal bone metabolism, featured by the imbalance between osteoblastic bone formation and osteoclastic bone resorption. Stem cell-based therapies have been demonstrated to improve osteoporosis treatment. Previously, the linear furanocoumarin heraclenin was reported to enhance osteoblast differentiation and mineralization in mouse mesenchymal stem cells (MSCs), suggesting its potential for osteogenic differentiation and bone regeneration. Our study was designed to confirm the promotive role of heraclenin on osteogenic differentiation of human bone MSCs (BMSCs) and explore the underlying mechanisms. METHODS: Human BMSCs were treated for 24, 48, and 72h with heraclenin (5, 10, 20, 40, and 80 µM), and cell viability was determined by Cell Counting Kit-8 (CCK-8) assay. To further evaluate the cytotoxicity of heraclenin, cell suspension obtained from BMSCs treated with heraclenin (5, 10, and 20 µM) for 72h was subjected to a MUSE™ cell analyzer for cell viability and count assay. BMSCs were incubated in osteogenic induction medium for 7 days. Then, osteogenic differentiation and mineralization of BMSCs were assessed through alkaline phosphatase (ALP) and Alizarin Red S staining. The expression of osteogenesis markers including ALP, osteocalcin (OCN), osterix (OSX), and runt-related transcription factor 2 (RUNX2) was detected via reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting. The effects of heraclenin on the RhoA/ROCK pathway were estimated through western blotting. Y-27632, the ROCK inhibitor, was used to confirm the role of the RhoA/ROCK pathway in heraclenin-mediated osteogenic differentiation of BMSCs. RESULTS: Heraclenin (5-80 µM) was non-toxic on human BMSCs. Heraclenin treatment (5-20 µM) dose-dependently enhanced ALP activity and calcium deposition. Furthermore, heraclenin promoted ALP, OCN, OSX, and RUNX2 mRNA and protein expression. Mechanically, heraclenin treatment increased RhoA and ROCK1 mRNA expression, stimulated the translocation of ROCK from the cytosolic to the membrane fraction, and elevated the protein levels of phosphorylated cofilin (p-cofilin) and active RhoA. Additionally, treatment with Y-27632 overturned the promotion of heraclenin on ALP activity, calcium deposition, the expression of osteogenesis markers, and the RhoA/ROCK signaling pathway. CONCLUSION: Heraclenin facilitates the osteogenic differentiation of human BMSCs through the activation of the RhoA/ROCK pathway.

Hypophysitis after COVID-19 vaccination in a patient with Rathke's cleft cyst: A case report.

With the widespread vaccination of COVID-19 vaccine, a few cases have been reported that COVID-19 vaccine may cause endocrine disorders. A 59-y-old man presented with a loss of appetite after the first COVID-19 vaccination, which resolved spontaneously after 3 d. After the second COVID-19 vaccination, the symptoms including the loss of appetite, nausea, and vomiting reappeared and worsened along with loss of vision. He was found to have severe hyponatremia, and further investigations revealed secondary adrenal insufficiency, secondary hypothyroidism and Rathke's cleft cyst. The patient responded well to glucocorticoid and levothyroxine supplementation, and at 1-y follow-up the patient developed hypogonadism. We hypothesize that hypophysitis is probably induced by COVID-19 vaccine and report the rare but serious adverse reactions for early recognition and intervention.