A dual-prodrug nanogel combining Vorinostat and Pyropheophorbide a for a high efficient photochemotherapy.

The challenges posed by intractable relapse and metastasis in cancer treatment have led to the development of various forms of photodynamic therapy (PDT). However, traditional drug delivery systems, such as virus vectors, liposomes, and polymers, often suffer from issues like desynchronized drug release, carrier instability, and drug leakage during circulation. To address these problems, we have developed a dual-prodrug nanogel (PVBN) consisting of Pyro (Pyropheophorbide a) and SAHA (Vorinostat) bound to BSA (Bovine Serum Albumin), which facilitates synchronous and spontaneous drug release in situ within the lysosome. Detailed results indicate that PVBN-treated tumor cells exhibit elevated levels of ROS and Acetyl-H3, leading to necrosis, apoptosis, and cell cycle arrest, with PDT playing a dominant role in the synergistic therapeutic effect. Furthermore, the anti-tumor efficacy of PVBN was validated in melanoma-bearing mice, where it significantly inhibited tumor growth and pulmonary metastasis. Overall, our dual-prodrug nanogel, formed by the binding of SAHA and Pyro to BSA and releasing drugs within the lysosome, represents a novel and promising strategy for enhancing the clinical efficacy of photochemotherapy.

Bauxite residue (red mud) treatment: Current situation and promising solution.

Bauxite residue, an industrial solid waste generated during alumina production, with over 80 % of bauxite residue worldwide being accumulated around alumina plants, which occupying a significant amount of land resources and posing a threat to the natural environment in the surrounding areas. This paper reviews recent advances in extracting valuable resources from bauxite residue, and its applications in building materials, environmental adsorbents, energy storage materials, and soil alkalinization. It also highlighted the main problem existing in these researches, which is the inability of the existing single processes to achieve the comprehensive utilization of various types of bauxite residue or maximize the utilization of bauxite residue components, resulting in a low comprehensive utilization rate and insignificant absorption effects of bauxite residue. To address these issues, we proposed a strategy of classifying and utilizing bauxite residue based on its components and establishing a multi-industry application system, involving sectors such as steel and building materials. This collaborative approach aims to handle various types of bauxite residue more effectively. Additionally, we suggest selecting suitable treatment methods based on the specific characteristics of bauxite residue and implementing measures to promote its comprehensive and large-scale utilization.

Compressive Properties of Basalt Fibers and Polypropylene Fiber-Reinforced Lightweight Concrete.

With the development of high-rise and large-scale modern structures, traditional concrete has become a design limitation due to its excessive dead weight. High-strength lightweight concrete is being emphasized. Lightweight concrete has low density and the characteristics of a brittle material. This is an important factor affecting the strength and ductility of the lightweight concrete. To improve these shortcomings and proffer solutions, a three-phase composite lightweight concrete was prepared using a combination of tumbling and molding methods. This paper investigates the various influencing factors such as the stacking volume fraction of GFR-EMS, the type of fiber, and the content and length of fiber in the matrix. Studies have shown that the addition of fibers significantly increases the compressive strength of the concrete. The compressive strength of concrete with a 12 mm basalt fiber (BF) (1.5%) admixture is 9.08 MPa, which is 62.43% higher than that of concrete without the fiber admixture. The compressive strength was increased by 27.53 and 21.88% compared to concrete containing 3 mm BF (1.5%) and 0.5% BF (12 mm), respectively. Fibers can fill the pore defects within the matrix. Mutually overlapping fibers easily form a network structure to improve the bond between the cement matrix and the aggregate particles. The compressive strength of lightweight concrete with the addition of BF was 16.71% higher than that with the addition of polypropylene fiber (PPF) with the same length and content of fibers. BF has been shown to be more effective in improving the mechanical properties of concrete. In this work, the compressive mechanism and optimum preparation parameters of a three-phase composite lightweight concrete were analyzed through compression tests. This provides some insights into the development of lightweight concrete.

SVDF: enhancing structural variation detect from long-read sequencing via automatic filtering strategies.

Structural variation (SV) is an important form of genomic variation that influences gene function and expression by altering the structure of the genome. Although long-read data have been proven to better characterize SVs, SVs detected from noisy long-read data still include a considerable portion of false-positive calls. To accurately detect SVs in long-read data, we present SVDF, a method that employs a learning-based noise filtering strategy and an SV signature-adaptive clustering algorithm, for effectively reducing the likelihood of false-positive events. Benchmarking results from multiple orthogonal experiments demonstrate that, across different sequencing platforms and depths, SVDF achieves higher calling accuracy for each sample compared to several existing general SV calling tools. We believe that, with its meticulous and sensitive SV detection capability, SVDF can bring new opportunities and advancements to cutting-edge genomic research.

The CEBPB+ glioblastoma subcluster specifically drives the formation of M2 tumor-associated macrophages to promote malignancy growth.

Rationale: The heterogeneity of tumor cells within the glioblastoma (GBM) microenvironment presents a complex challenge in curbing GBM progression. Understanding the specific mechanisms of interaction between different GBM cell subclusters and non-tumor cells is crucial. Methods: In this study, we utilized a comprehensive approach integrating glioma single-cell and spatial transcriptomics. This allowed us to examine the molecular interactions and spatial localization within GBM, focusing on a specific tumor cell subcluster, GBM subcluster 6, and M2-type tumor-associated macrophages (M2 TAMs). Results: Our analysis revealed a significant correlation between a specific tumor cell subcluster, GBM cluster 6, and M2-type TAMs. Further in vitro and in vivo experiments demonstrated the specific regulatory role of the CEBPB transcriptional network in GBM subcluster 6, which governs its tumorigenicity, recruitment of M2 TAMs, and polarization. This regulation involves molecules such as MCP1 for macrophage recruitment and the SPP1-Integrin αvß1-Akt signaling pathway for M2 polarization. Conclusion: Our findings not only deepen our understanding of the formation of M2 TAMs, particularly highlighting the differential roles played by heterogeneous cells within GBM in this process, but also provided new insights for effectively controlling the malignant progression of GBM.

Rare secondary hypertension caused by compound heterozygous CYP17A1 mutations: a case report.

Background: 17α-Hydroxylase deficiency, a rare form of congenital adrenal hyperplasia, presents diagnostic and treatment challenges because of the limited number of cases reported. Case summary: This report discusses the case of a 17-year-old Chinese girl who suffered from unexplained dizziness, headaches, and high blood pressure. She had amenorrhoea during puberty and had been diagnosed with ovarian delay. Initially, she was diagnosed with hypertension and received three antihypertensive medications. However, her blood pressure remained poorly controlled. Gene sequencing revealed 17α-hydroxylase deficiency caused by compound heterozygous mutations in CYP17A1. One of the mutation sites, potentially novel, has not been reported previously. Subsequently, dexamethasone therapy was initiated, her blood pressure was controlled, and the symptoms disappeared. During the 1-year follow-up, her blood pressure remained normal, and the symptoms did not recur. Discussion: 17α-Hydroxylase deficiency is a rare cause of secondary hypertension. Despite the low prevalence, it should not be overlooked in younger patients.

Deciphering the impact of nitrogen morphologies distribution on nitrogen and biomass accumulation in tobacco plants.

Background and aims: Nitrogen (N) distribution in plants is intricately linked to key physiological functions, including respiration, photosynthesis, structural development, and nitrogen storage. However, the specific effects of different N morphologies on N accumulation and plant growth are poorly understood. Our research specifically focused on determining how different N morphologies affect N absorption and biomass accumulation. Methods: This study elucidated the impact of different application rates (CK: 0 g N/plant; T1: 4 g N/plant; T2: 8 g N/plant) of N fertilizer on N and biomass accumulation in tobacco cultivars Hongda and K326 at different growth stages. Results: Our findings emphasize the critical role of N distribution in various plant parts, including leaves, stems, and roots, in determining the complex mechanisms of N and biomass accumulation in tobacco. We found that in relation to total N, a greater ratio of water-soluble N (N w) in leaves facilitated N accumulation in leaves. In contrast, an increased ratio of SDS (detergent)-insoluble N (N in-SDS) in leaves and non-protein N (N np) in roots hindered this increase. Additionally, our results indicate that a greater proportion of N np in leaves has a negative impact on biomass accumulation in leaves. Furthermore, elevated levels of N in-SDS, N w, and N np in roots, and N np in leaves adversely affected biomass accumulation in tobacco leaves. The Hongda cultivar exhibited greater biomass and N accumulation abilities as compared to K326. Conclusions: Our findings highlight the significant role of distribution of N morphologies on plant growth, as well as N and biomass accumulation in tobacco plants. Understanding N distribution allows farmers to optimize N application, minimizing environmental losses and maximizing yield for specific cultivars. These insights advance sustainable agriculture by promoting efficient resource use and reducing environmental impact.

Five Karenia species along the Chinese coast: With the description of a new species, Karenia hui sp. nov. (Kareniaceae, Dinophyta).

Dinoflagellates within the genus Karenia are well known for their potential to cause harmful algal blooms and induce detrimental ecological consequences. In this study, five Karenia species, Karenia longicanalis, Karenia papilionacea, Karenia mikimotoi, Karenia selliformis, and a new species, Karenia hui sp. nov., were isolated from Chinese coastal waters. The new species exhibits the typical characteristics of the genus Karenia, including a linear apical groove and butanoyl-oxyfucoxanthin as the major accessory pigment. It is distinguished from the other Karenia species by a wide-open sulcal intrusion onto the epicone, a conical epicone with an apical crest formed by the rim of the apical groove, and a hunchbacked hypocone. It is most closely related to Karenia cristata, with a genetic divergence of 3.16 % (22 bp out of 883 bp of LSU rDNA). Acute toxicity tests indicated that the five Karenia species from China are all toxic to marine medaka Oryzias melastigma. Karenia selliformis and K. hui were very toxic to O. melastigma, resulting in 100 % mortality within 4 h and 24 h, respectively. Further analysis by high-performance liquid chromatography revealed that four species, K. selliformis, K. longicanalis, K. papilionacea and K. mikimotoi were capable of producing Gymnodimine-A (GYM-A). The highest GYM-A content was in K. selliformis (strain HK-43), in which the value was 889 fg/cell. No GYM-A was detected in the new species K. hui, however and its toxin remains unknown. Below we provide a comprehensive report of the morphology, phylogeny, pigment composition, and toxicity profiles of Karenia species along the Chinese coast. These findings contribute new insights for monitoring of Karenia species, with important toxicological and ecological implications.

GSDME promotes MASLD by regulating pyroptosis, Drp1 citrullination-dependent mitochondrial dynamic, and energy balance in intestine and liver.

Dysregulated metabolism, cell death, and inflammation contribute to the development of metabolic dysfunction-associated steatohepatitis (MASH). Pyroptosis, a recently identified form of programmed cell death, is closely linked to inflammation. However, the precise role of pyroptosis, particularly gasdermin-E (GSDME), in MASH development remains unknown. In this study, we observed GSDME cleavage and GSDME-associated interleukin-1ß (IL-1ß)/IL-18 induction in liver tissues of MASH patients and MASH mouse models induced by a choline-deficient high-fat diet (CDHFD) or a high-fat/high-cholesterol diet (HFHC). Compared with wild-type mice, global GSDME knockout mice exhibited reduced liver steatosis, steatohepatitis, fibrosis, endoplasmic reticulum stress, lipotoxicity and mitochondrial dysfunction in CDHFD- or HFHC-induced MASH models. Moreover, GSDME knockout resulted in increased energy expenditure, inhibited intestinal nutrient absorption, and reduced body weight. In the mice with GSDME deficiency, reintroduction of GSDME in myeloid cells-rather than hepatocytes-mimicked the MASH pathologies and metabolic dysfunctions, as well as the changes in the formation of neutrophil extracellular traps and hepatic macrophage/monocyte subclusters. These subclusters included shifts in Tim4+ or CD163+ resident Kupffer cells, Ly6Chi pro-inflammatory monocytes, and Ly6CloCCR2loCX3CR1hi patrolling monocytes. Integrated analyses of RNA sequencing and quantitative proteomics revealed a significant GSDME-dependent reduction in citrullination at the arginine-114 (R114) site of dynamin-related protein 1 (Drp1) during MASH. Mutation of Drp1 at R114 reduced its stability, impaired its ability to redistribute to mitochondria and regulate mitophagy, and ultimately promoted its degradation under MASH stress. GSDME deficiency reversed the de-citrullination of Drp1R114, preserved Drp1 stability, and enhanced mitochondrial function. Our study highlights the role of GSDME in promoting MASH through regulating pyroptosis, Drp1 citrullination-dependent mitochondrial function, and energy balance in the intestine and liver, and suggests that GSDME may be a potential therapeutic target for managing MASH.

Comparison of case-based and lecture-based learning in dental fluorosis diagnostic ability with visual analog scale assessment.

OBJECTIVE: This study aimed to compare the impact of case-based learning (CBL) versus lecture-based learning (LBL) on dental students' clinical decision-making regarding DF severity using Visual Analog Scale (VAS) scoring. METHODS: Eighty first-year graduate dental students were randomly assigned to either the CBL (n = 38) or LBL (n = 42) groups. Both groups received instruction on DF diagnosis, with CBL involving small group sessions analyzing real cases and LBL involving traditional lectures. Effectiveness was assessed by presenting 32 dental fluorosis cases with Thylstrup-Fejerskov Index (TSIF) scores ranging from 0 to 7 through slide presentations to both groups for VAS assessment. Five evaluators of each group randomly selected were asked to repeat the rating 2 weeks later. Statistical analysis included two-way ANOVA for group and gender differences, intra-class correlation coefficient (ICC) for reliability, and Spearman correlation coefficients for validity. RESULTS: Variations in VAS scores were observed between CBL and LBL groups, with no significant gender impact. Excellent inter- and intra-evaluator agreement was found for VAS scoring in both groups, indicating its reliability. Validation against established indices (such as DI and TSIF) demonstrated strong correlations, with CBL students exhibiting higher correlations. CONCLUSIONS: CBL enhances students' clinical decision-making and proficiency in DF diagnosis, as evidenced by more consistent and accurate VAS scoring compared to LBL. These findings highlight the importance of innovative educational strategies in dental curricula, with implications for improving training quality and clinical outcomes. TRIAL REGISTRATION: The study was registered at the Clinical Research Center, Hospital of Stomatology, Wuhan University (Registration code: HGGC-036).

Clinical Characteristics of Lung Abscess Caused by Streptococcus Constellatus Infection.

BACKGROUND: This study aimed to understand the clinical characteristics of pulmonary abscess caused by Streptococcus constellatus infection. METHODS: The clinical manifestations, laboratory examination, drug sensitivity, chest CT manifestations, and treatment and prognosis of patients with pulmonary abscess caused by Streptococcus constellatus infection were retrospectively collected and analyzed. RESULTS: A total of 9 cases of pulmonary abscess caused by Streptococcus constellatus infection were confirmed; one case was confirmed by traditional cultures, while metagenomic next-generation sequencing (mNGS) confirmed the other 8 cases. All of the 9 patients had different degrees of cough, sputum, fever, chest pain, and/or dyspnea, and the physical examination showed fast breathing, reduced respiratory sound, or moist rales on the affected side. In laboratory tests, 8 patients had elevated white blood cells and hypoproteinemia upon admission. Blood gas analysis showed an oxygenation index < 300. The antimicrobial susceptibility testing results in 1 patient with culture-confirmed pathogen diagnosis showed that Streptococcus constellatus was susceptible to ampicillin, penicillin G, cefotaxime, ceftriaxone, cefepime, meropenem, chloramphenicol, linezolid, levofloxacin, and vancomycin and resistant to tetracycline and clindamycin. Relevant antibiotic resistance genes were not detected by mNGS in the 8 patients with negative culture and positive mNGS results. A chest CT showed lung consolidation or cavity formation in 9 patients admitted to the hospital, and 5 patients had pleural effusion. 3 cases were admitted to the respiratory intensive care unit (RICU) and 6 cases were admitted to the general ward. There were 3 cases of nasal catheter oxygen inhalation, 1 case of mask oxygen inhalation, and 5 cases of non-invasive ventilator assisted ventilation. All patients received penicillin or respiratory quinolones anti-infection therapy, and 3 cases were treated with a thoracic closed drainage tube. All patients were discharged from the hospital after improvement, and the hospital stay was 15 - 23 days. CONCLUSIONS: Patients with pulmonary abscess caused by Streptococcus constellatus infection have an urgent condition and rapid progression. It is helpful to use mNGS combined with traditional culture as soon as possible to identify the pathogenic bacteria. Penicillin antibiotics should be the first choice for pulmonary abscess caused by a suspected Streptococcus constellatus infection. If a patient´s condition worsens during the treatment, especially for patients who have lesions involving the interlobar fissure or pleura, compressive atelectasis caused by pleural fluid formation or an increase in the amount of pleural effusion needs to be highly suspected.

Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial.

Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1-32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7-18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 .

Flow shear force destabilizes carotid plaques by affecting CHOP and GRP78 proteins.

BACKGROUND: Various factors, including blood, inflammatory, infectious, and immune factors, can cause ischemic stroke. However, the primary cause is often the instability of cervical arteriosclerosis plaque. It is estimated that 18-25% of ischemic strokes are caused by the rupture of carotid plaque.1 Plaque stability is crucial in determining patient prognosis. Developing a highly accurate, non-invasive, or minimally invasive technique to assess carotid plaque stability is crucial for diagnosing and treating stroke.Previous research by our group has demonstrated that the expression levels of CHOP (C/EBP homologous protein) and GRP78 (glucose-regulated protein 78) are correlated with the stability of atherosclerotic plaques.2 OBJECT: This research assesses changes in GRP78 and CHOP expressions in human umbilical vein endothelial cells(HUVEC) following experiments within the hemodynamic influencing factors test system. Additionally, it includes conducting an empirical study on the impact of blood flow shear force on the stability of human carotid atherosclerotic plaques. The objective is to explore the implications of blood flow shear force on the stability of carotid atherosclerotic plaques. METHOD: The hemodynamic influencing factors test bench system was configured with low (Group A, 4 dyns/cm²), medium (Group B, 8 dyns/cm²), and high shear force groups (Group C, 12 dyns/cm²). Relative expression levels of GRP78 and CHOP proteins in human umbilical vein endothelial cells were measured using Western blot analysis, and quantitative analysis of GRP78 and CHOP mRNA was conducted using RT-qPCR. Meanwhile, plaques from 60 carotid artery patients, retrieved via Carotid Endarterectomy (CEA), were classified into stable (S) and unstable (U) groups based on pathological criteria. Shear force at the carotid bifurcation was measured preoperatively using ultrasound. Western blot and RT-qPCR were used to analyze the relative expression levels of GRP78 and CHOP proteins and mRNA, respectively, in the plaque specimens from both groups. RESULT: Expression levels of GRP78, CHOP proteins, and their mRNAs were assessed in groups A, B, and C via Western blot and RT-qPCR. Results showed that in the low-shear group, all markers were elevated in group A compared to groups B and C. Statistical analysis revealed significantly lower shear forces at the carotid bifurcation in group U compared to group S. In group U plaques, GRP78 and CHOP expressions were significantly higher in group U than in group S. CONCLUSION: Blood flow shear forces variably affect the expression of GRP78 and CHOP proteins, as well as their mRNA levels, in vascular endothelial cells. The lower the shear force and fluid flow rate, the higher the expression of GRP78 and CHOP, potentially leading to endoplasmic reticulum stress(ERS), which may destabilize the plaque.

Programmed cell death regulator BAP2 is required for IRE1-mediated unfolded protein response in Arabidopsis.

Environmental and physiological situations can challenge the balance between protein synthesis and folding capacity of the endoplasmic reticulum (ER) and cause ER stress, a potentially lethal condition. The unfolded protein response (UPR) restores ER homeostasis or actuates programmed cell death (PCD) when ER stress is unresolved. The cell fate determination mechanisms of the UPR are not well understood, especially in plants. Here, we integrate genetics and ER stress profiling with natural variation and quantitative trait locus analysis of 350 natural accessions of the model species Arabidopsis thaliana. Our analyses implicate a single nucleotide polymorphism to the loss of function of the general PCD regulator BON-ASSOCIATED PROTEIN2 (BAP2) in UPR outcomes. We establish that ER stress-induced BAP2 expression is antagonistically regulated by the UPR master regulator, inositol-requiring enzyme 1 (IRE1), and that BAP2 controls adaptive UPR amplitude in ER stress and ignites pro-death mechanisms in conditions of UPR insufficiency.

Anthropogenic activity shapes the assemble and co-occurrence pattern of microbial communities in fishing harbors around the Bohai Economic Circle.

This study aimed to elucidate the effects of coastal environmental stress on the composition of sediment bacterial communities and their cooccurrence patterns in fishing harbors around the Bohai Economic Circle, China. Compared with the natural sea area, fishing harbors contained higher levels of organic pollution (organic pollution index = 0.12±0.026) and considerably reduced bacterial richness and evenness. The distributions of sediment microbial communities clustered along the pollutant concentration gradients across fishing harbors. Betaproteobacteria dominated (76%) organically polluted fishing harbors, which were mostly disturbed by anthropogenic activities. However, the harbors also revealed the absence of numerous pathogenic (Coxiella and Legionella) and photosynthetic (Synechococcus and Leptolyngbya) bacteria. Abundant genera, including Thiobacillus and Arenimonas, exhibited a positive correlation with total phosphorus and a negative correlation with total nitrogen in sediments. Meanwhile, Sulfurovum, Psychrobacter, and Woeseia showed the opposite trend. Pollutant accumulation and anthropogenic activities caused the decrease in the sediment microbial diversity and dispersal ability and promoted convergent evolution. Severely polluted harbors with simplified cooccurrence networks revealed the presence of destabilized microbial communities. In addition, the modularity of bacterial networks decreased with organic pollution. Our results provide important insights into the adjustment mechanism of microbial communities to community organization and functions under environmental pollution stress. Overall, this study enhanced our understanding of how microbial communities in coastal sediments adapted and survived amidst anthropogenic activities like oily effluent discharges from large ships, wash water, domestic sewage, garbage, and fisheries wastes. It also examined their resilience to future contamination.

Podophyllotoxin via SIRT1/PPAR /NF-κB axis induced cardiac injury in rats based on the toxicological evidence chain (TEC) concept.

BACKGROUND: The study of cardiotoxicity of drugs has become an important part of clinical safety evaluation of drugs. It is commonly known that podophyllotoxin (PPT) and its many derivatives and congeners are broad-spectrum pharmacologically active substances. Clinical cardiotoxicity of PPT and its derivatives has been raised, basic research on the mechanism of cardiotoxicity remains insufficient. PURPOSE: In present study, our group's innovative concept of toxicological evidence chain (TEC) was applied to reveal the cardiac toxicity mechanism of PPT by targeted metabolomics, TMT-based quantitative proteomics and western blot. METHODS: The injury phenotype evidence (IPE) acquired from the toxicity manifestations, such as weight and behavior observation of Sprague-Dawley rat. The damage to rat hearts were assessed through histopathological examination and myocardial enzymes levels, which were defined as Adverse Outcomes Evidence (AOE). The damage to rat hearts was assessed through histopathological examination and myocardial enzyme levels, which were defined as evidence of adverse outcomes.Overall measurements of targeted metabolomics based on energy metabolism and TMT-based quantitative proteomics were obtained after exposure to PPT to acquire the Toxic Event Evidence (TEE). The mechanism of cardiac toxicity was speculated based on the integrated analysis of targeted metabolomics and TMT-based quantitative proteomics, which was verified by western blot. RESULTS: The results indicated that exposure to PPT could result in significant elevation of myocardial enzymes and pathological alterations in rat hearts. In addition, we found that PPT caused disorders in cardiac energy metabolism, characterized by a decrease in energy metabolism fuels. TMT-based quantitative proteomics revealed that the PPAR (Peroxisome proliferators-activated receptor) signaling pathway needs further study. It is worth noting that PPT may suppress the expression of SIRT1, subsequently inhibiting AMPK, decreasing the expression of PGC-1α, PPARα and PPARγ. This results in disorders of glucose oxidation, glycolysis and ketone body metabolism. Additionally, the increase in the expression of p-IKK and p-IκBα, leads to the nuclear translocation of NF-κB p65 from the cytosol, thus triggering inflammation. CONCLUSION: This study comprehensively evaluated cardiac toxicity of PPT and initially revealed the mechanism of cardiotoxicity,suggesting that PPT induced disorders of energy metabolism and inflammation via SIRT1/PPAR/NF-κB axis, potentially contributing to cardiac injury.

Enantioselective Ni-Catalyzed 1,2-Borylalkynylation of Unactivated Alkenes.

Enantioselective three-component difunctionalization of alkenes with boron reagents represents an attractive strategy for assembling three-dimensional chiral organoboron compounds. However, regio- and enantiocontrol comprise the pivot challenges in these transformations, which predominantly require the use of activated conjugated alkenes. Herein, by utilizing various carbonyl directing groups, including amides, sulfinamides, ketones, and esters, we succeed in realizing a nickel-catalyzed 1,2-borylalkynylation of unactivated alkenes to enable the simultaneous incorporation of a boron entity and an sp-fragment across the double bond. The products contain boryl, alkynyl, and carbonyl functional groups with orthogonal synthetic reactivities, offering three handles for further derivatization to access valuable intermediates. The utility of this ligand-enabled asymmetric protocol has been highlighted through the late-stage decoration of drug-relevant molecules.

Exploring the mechanism of enterotoxicity mediated by the microbiome-butyrate-PPAR axis in podophyllotoxin through the toxicological evidence chain (TEC) concept.

Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The underlying mechanisms by which PPT exerts its action remain largely elusive. This study aimed to evaluate the molecular mechanisms underlying PPT-induced enterotoxicity utilizing the concept of toxicological evidence chain. Changes in body weight, behavior, and histopathological and biochemical markers in rats were observed. Additionally, microbiome, metabolome, and transcriptome analyses were integrated to identify potential microorganisms, metabolic markers, and major pathways using a co-occurrence network. Our findings suggested that PPT induced pathological changes in rats, including weight loss, diarrhea, and inflammation accompanied by increased levels of IFN-γ, IL-5, IL-6, GRO/KC, and IL-12p70. The decrease in butyrate levels in the PPT group may be related to the enrichment of Firmicutes. The reduction of butyrate levels may impair the expression of PPARγ, subsequently promoting Escherichia-Shigella proliferation. Additionally, the suppression of PPARs pathway may result in the increased production of inflammatory factors, contributing to enterotoxicity. This study offers a novel understanding of the molecular mechanisms underlying PPT-induced enterotoxicity, making a significant contribution to developing strategies to mitigate PPT toxicity and prevent associated diseases.