Photoactive nanocatalysts as DTT-assisted BSA-AuNCs with enhanced oxidase-mimicking ability for sensitive fluorometric detection of antioxidants.

Redox imbalance and oxidative stress are increasingly recognized as significant factors in health disorders such as neurodegenerative disorders, premature aging and cancer. However, detecting antioxidant levels that is crucial for managing oxidative stress, can be challenging due to existing assays' limitations, such as insensitivity to thiol-containing antioxidants. This study presents a simple fluorescence-based assay for antioxidant detection employing the enhanced photocatalytic oxidase-like activity of dithiothreitol (DTT)-assisted bovine serum albumin (BSA)-stabilized gold nanoclusters (DTT@BSA-AuNCs). The reported nanozyme exhibits remarkable stability, versatility, and catalytic activity. Under LED irradiation, DTT@BSA-AuNCs generate singlet oxygen, which converts non-fluorescent thiamine to fluorescent thiochrome, utilizing dissolved oxygen for catalysis. Antioxidants inhibit thiochrome formation, leading to fluorescence quenching. This method enables sensitive detection of antioxidants such as ascorbic acid and glutathione with limits of detection of 0.08 µM and 0.32 µM, respectively, under neutral pH, outperforming previous studies. The assay successfully detects antioxidants in human saliva and cancer cell models. The DTT@BSA-AuNCs-based assay offers a cost-effective, sensitive, and straightforward approach for detecting antioxidants in biological samples, facilitating improved monitoring of oxidative stress in various diseases.

Phytochemicals, Two New Sulphur Glycosides and Two New Natural Products, from Shepherd's Purse Seed and Their Activities.

Two new sulfur glycosides, bursapastoris A-B (3-4), were extracted and isolated from shepherd's purse seed, along with two new natural products, 11-(methylsulfinyl)undecanoic acid (2) and 10-(methylsulfinyl)decanoic acid (1). Their structures were determined though infrared spectroscopy, one-dimensional nuclear magnetic resonance (1H and 13C), and electrospray ionization mass spectrometry. Additionally, the structures of 3-4 were further identified by two-dimensional nuclear magnetic resonance (HMBC, HSQC, 1H-1H COSY, and NOESY). Compounds 1-4 showed relatively favorable docking to NF-κB. Unfortunately, we only discovered that compound 1-4 had weak anti-radiation activity at present. Therefore, further research regarding the biological activity of these organosulfur compounds is required at a later stage.

The Inhibitory Impact of a Co-Assembly Gel with Natural Carrier-Free Binary Small Molecules, as Used in Traditional Chinese Medicine, on the Viability of SW1990 Cells.

Chinese herbs are a huge treasure trove of natural products and an important source of many active molecules. The theory of traditional Chinese medicine compatibility (TCMC) is widely applied in clinical practice, but its mechanism is still ambiguous. This study aims to open a new window for this predicament by studying the interaction between the main active ingredients from a drug pair. Carrier-free assembly of natural products improves the shortcomings of traditional nanodelivery systems and opens a new path for the development of new nanomaterials. The drug pair "Pueraria and Hedyotis diffusa" has been commonly used in clinical practice, with a predominant therapeutic effect. This study is devoted to the study of the binary small molecule co-assembly of the main active molecules from the drug pair. In this study, we introduce a carrier-free composite gel, formed by the co-assembly of puerarin (PUE) and deacetylasperulosidic acid (DAA) via non-covalent bonds including π-π packing, intermolecular hydrogen bonding, and C=O π interactions. With a strain point 7-fold higher than that of P gel, the P - D gel exhibited favorable rheological properties. The survival rate of SW1990 cells in the P - D group was only 21.39% when the concentration of administration reached 200 µM. It thus demonstrated activity in inhibiting SW1990 cells' survival, suggesting potential in combating pancreatic cancer. Furthermore, this research offers a valuable concept for enhancing the mechanical properties and bioactivity of hydrogel materials through the utilization of a multi-component natural small molecule co-assembly approach. More importantly, this provides new ideas and methods for the treatment of pancreatic cancer and the analysis of traditional Chinese medicine compatibility theory.

Repurposing existing drugs for the treatment ofCOVID-19/SARS-CoV-2: A review of pharmacological effects and mechanism of action.

Following the coronavirus disease-2019 outbreak caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an ongoing need to seek drugs that target COVID-19. First off, novel drugs have a long development cycle, high investment cost, and are high risk. Second, novel drugs must be evaluated for activity, efficacy, safety, and metabolic performance, contributing to the development cycle, investment cost, and risk. We searched the Cochrane COVID-19 Study Register (including PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and WHO COVID-19 Coronaviral Disease Global Literature to identify completed and ongoing studies as of February 20, 2024. We evaluated the pharmacological effects, in vivo and in vitro data of the 16 candidates in the paper. The difficulty of studying these candidates in clinical trials involving COVID-19 patients, dosage of repurposed drugs, etc. is discussed in detail. Ultimately, Metformin is more suitable for prophylactic administration or mildly ill patients; the combination of Oseltamivir, Tamoxifen, and Dexamethasone is suitable for moderately and severely ill patients; and more clinical trials are needed for Azvudine, Ribavirin, Colchicine, and Cepharanthine to demonstrate efficacy.

The Orphan G Protein-Coupled Receptor GPR52 is a Novel Regulator of Breast Cancer Multicellular Organization.

G protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors and transmit critical signals from the extracellular to the intracellular spaces. Transcriptomic data of resected breast tumors shows that low mRNA expression of the orphan GPCR GPR52 correlates with reduced overall survival in breast cancer patients, leading to the hypothesis that loss of GPR52 supports breast cancer progression. CRISPR-Cas9 was used to knockout GPR52 in human triple-negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231, and in the non-cancerous breast epithelial cell line, MCF10A. Loss of GPR52 was found to be associated with increased cell-cell interaction in 2D cultures, altered 3D spheroid morphology, and increased propensity to organize and invade collectively in Matrigel. Furthermore, GPR52 loss was associated with features of EMT in MDA-MB-468 cells. To determine the in vivo impact of GPR52 loss, MDA-MB-468 cells were injected into zebrafish and loss of GPR52 was associated with a greater total cancer area compared to control cells. RNA-sequencing and proteomic analyses of GPR52-null breast cancer cells reveal an increased cAMP signaling signature. Consistently, we found that treatment of wild-type (WT) cells with forskolin, which stimulates production of cAMP, induces some phenotypic changes associated with GPR52 loss, and inhibition of cAMP production rescued some of the GPR52 KO phenotypes. Overall, our results reveal GPR52 loss as a potential mechanism by which breast cancer progression may occur and support the investigation of GPR52 agonism as a therapeutic option in breast cancer.

Identifying Associations between Small Nucleolar RNAs and Diseases via Graph Convolutional Network and Attention Mechanism.

Research has shown that small nucleolar RNAs (snoRNAs) play crucial roles in various biological processes, and understanding disease pathogenesis by studying their relationship with diseases is beneficial. Currently, known associations are insufficient, and conventional biological experiments are costly and time-consuming. Therefore, developing efficient computational methods is crucial for identifying potential snoRNA-disease associations. In this paper, a method to identify snoRNA-disease associations based on graph convolutional network and multi-view graph attention mechanism (GCASDA) is proposed. Firstly, the similarity matrices of snoRNAs and diseases are calculated based on biological entity-related information, and the weights of the edges between the snoRNA nodes and the disease nodes are supplemented by random forest. Then two homogeneous graphs and one heterogeneous graph are constructed. Subsequently, different types of embedded features are extracted from the graphs using specific graph convolutional network structure and integrated through a multi-view graph attention mechanism to obtain node embedded feature representations. Finally, for each pair of nodes, in addition to their global features, node interaction features are passed together to a multilayer perceptron neural network (MLP) to identify snoRNA-disease associations. Experimental results show that GCASDA achieves 0.9356 and 0.9294 in AUC and AUPR, respectively, and significantly outperformed other state-of-the-art methods on the basis of different evaluation metrics. Furthermore, the case study could further demonstrate the realistic feasibility of GCASDA.

Re-watering solution facilitates seed germination and seedling growth of Carex schmidtii: Implication for species re-introduction in degraded semi-arid wetlands.

Water deficiency threatens the health and function of wetlands in semi-arid areas. Optimum re-watering is an effective method for close-to-natural restoration to mitigate wetland degradation. Although the ecological importance of optimal re-watering as a nature-based solution for promoting wetland plant growth has been widely recognized, the response mechanisms of seed germination and seedling growth to re-watering are still poorly understood despite their decisive impact on plant life history. To fill this gap, this study compared the characteristics of seed germination and seedling growth in Carex schmidtii under initial water content with three levels (30%, 50%, and 70%) and five re-watering treatments (maintained at constant water content and re-watering to 100% on 7th, 14th, 21st, and 28th day). Moreover, the degree of reserve mobilization during four germination stages (seed suckering, sprouting, 20% germination, and seedling growth) was investigated. The results showed that water deficiency and re-watering treatments significantly affected C. schmidtii seed germination, seedling growth, and reserve mobilization. Compared with the other treatments, 50% moisture content and re-watering to 100% on the 14th day (50%-RT3) treatment significantly improved germination traits (germination rate, daily germination rate, germination index, and vigor index) and seedling growth characteristics (shoot length, root length, shoot biomass, root biomass, and total biomass). Furthermore, the degree of mobilization of starch, soluble protein, fat, and soluble sugar accumulation in C. schmidtii seeds under 50%-RT3 was higher than that in the other treatments. The structural equation model showed that the characteristics of seed germination and seedling growth of C. schmidtii were directly related to water deficiency and re-watering treatments, whereas reserve mobilization indirectly affected seed germination and seedling growth. These findings demonstrated that water deficiency and re-watering treatments have a crucial regulatory effect on seed germination and seedling growth of wetland plant species through a dual mechanism. This study provides information for the formulation of an optimum re-watering strategy for wetland vegetation restoration in semi-arid areas of the world.

Development of bovine serum albumin-modified Fe3O4 embedded in porous α-ketoglutaric acid/chitosan (BSA/Fe3O4@KA/CS): A magnetically targeted hemostatic dressing for deep and irregular wounds.

Severe bleeding from deep and irregular wounds poses a significant challenge in prehospital and surgical settings. To address this issue, we developed a novel chitosan-based hemostatic dressing with a magnetic targeting mechanism using Fe3O4, termed bovine serum albumin-modified Fe3O4 embedded in porous α-ketoglutaric acid/chitosan (BSA/Fe3O4@KA/CS). This dressing enhances hemostasis by magnetically guiding the agent to the wound site. In vitro, the hemostatic efficacy of BSA/Fe3O4@KA/CS is comparable to that of commercial chitosan (Celox™) and is not diminished by the modification. In vivo, BSA/Fe3O4@KA/CS demonstrated superior hemostatic performance and reduced blood loss compared to Celox™. The hemostatic mechanism of BSA/Fe3O4@KA/CS includes the concentration of solid blood components through water absorption, adherence to blood cells, and activation of the endogenous coagulation pathway. Magnetic field targeting is crucial in directing the dressing to deep hemorrhagic sites. Additionally, safety assessments have confirmed the biocompatibility and biodegradability of BSA/Fe3O4@KA/CS. In conclusion, we introduce a novel approach to modify chitosan using magnetic guidance for effective hemostasis, positioning BSA/Fe3O4@KA/CS as a promising candidate for managing various wounds.

Icaritin exhibits potential drug-drug interactions through the inhibition of human UDP-glucuronosyltransferase in vitro.

Icaritin is a prenylflavonoid derivative of the genus Epimedium (Berberidaceae) and has a variety of pharmacological actions. Icaritin is approved by the National Medical Products Administration as an anticancer drug that exhibits efficacy and safety advantages in patients with hepatocellular carcinoma cells. This study aimed to evaluate the inhibitory effects of icaritin on UDP-glucuronosyltransferase (UGT) isoforms. 4-Methylumbelliferone (4-MU) was employed as a probe drug for all the tested UGT isoforms using in vitro human liver microsomes (HLM). The inhibition potentials of UGT1A1 and 1A9 in HLM were further tested by employing 17ß-estradiol (E2) and propofol (PRO) as probe substrates, respectively. The results showed that icaritin inhibits UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A10, 2B7, and 2B15. Furthermore, icaritin exhibited a mixed inhibition of UGT1A1, 1A3, and 1A9, and the inhibition kinetic parameters (Ki) were calculated to be 3.538, 2.117, and 0.306 (µM), respectively. The inhibition of human liver microsomal UGT1A1 and 1A9 both followed mixed mechanism, with Ki values of 2.694 and 1.431 (µM). This study provides supporting information for understanding the drug-drug interaction (DDI) potential of the flavonoid icaritin and other UGT-metabolized drugs in clinical settings. In addition, the findings provide safety evidence for DDI when liver cancer patients receive a combination therapy including icaritin.

Effect of different drying methods on the structure and properties of porous starch.

In order to investigate the effects of different drying methods on the properties of porous starch. The present study used four drying methods, namely hot air drying (HD), spray drying (SPD), vacuum freeze drying (FD) and supercritical carbon dioxide drying (SCD) to prepare maize and kudzu porous starch. Findings indicated that the physicochemical properties (e.g., morphology, crystallinity, enthalpy value, porosity, surface area and water absorption capacity as well as dye absorption capacity, particle size) of porous starch were significantly affected by the drying method. Compared with other samples, SCD-treated porous starch exhibited the highest surface areas of the starch (2.943 and 3.139 m2/g corresponding to kudzu and maize, respectively), amylose content (22.02 % and 16.85 % corresponding to kudzu and maize, respectively), MB and NR absorption capacity (90.63 %, 100.26 % and 90.63 %, 100.26 %, corresponding to kudzu ad maize, respectively), and thermal stability, whereas HD-treated porous starch showed the highest water-absorption capacity (123.8 % and 131.31 % corresponding to kudzu and maize, respectively). The dye absorption of the maize and kudzu porous starch was positively correlated with surface area, according to Pearson's correlation analysis. Therefore, in this study, our aim was to explore the effects of different drying methods on the Structure and properties of porous starch, and provide reference for selecting the best drying method for its application in different fields.

Design and Synthesis of Dimethylaminomethyl-Substituted Curcumin Derivatives: Potent Anti-Inflammatory, Anti-Oxidant, and Radioprotection Activity, Improved Aqueous Solubility Compared with Curcumin.

Although the wide variety of bioactivities of curcumin has been reported by researchers, the clinical application of curcumin is still limited due to its poor aqueous solubility. In view of this, a series of dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized (compounds 1-15). Acetate of these derivatives were prepared (compounds 1a-15a). The Mannich reaction and aldol condensation reaction are the main reactions involved in this study. Compounds 6, 10, 12, 3a, 5a, 6a, 7a, 8a, 10a, 11a, 12a, 13a, 14a, and 15a exhibited better in vitro anti-inflammatory activity compared to curcumin in the RAW264.7 cell line. Compounds 5, 1a, 5a, 8a, and 12a exhibited better in vitro antioxidant activity compared to curcumin in the PC 12 cell line. Compounds 11, 13, 5a, 7a, and 13a exhibited better in vitro radiation protection compared to curcumin in the PC 12 cell line. The aqueous solubilities of all the curcumin derivative acetates were greatly improved compared to curcumin.

A review on triterpenoid and triterpenoid saponins from Xanthoceras sorbifolium Bung.

Xanthoceras sorbifolium Bunge, also known as Tu-Mu-Gua and Wen-Dan-Ge-Zi, has several applications. Clinical data and experimental studies have shown anti-tumor, anti-inflammatory, anti-bacterial, and anti-oxidant properties of Xanthoceras sorbifolium Bunge that inhibits prostate hyperplasia, lowers blood pressure and lipid level, and treats enuresis and urinary incontinence. It also has neuroprotective effects and can treat Alzheimer's disease and Parkinson's syndrome. The research on the chemical composition and pharmacological effects of Xanthoceras sorbifolium Bunge has been increasing. Triterpenoid and triterpenoid saponins are the main constituents in Xanthoceras sorbifolium Bunge and exhibit biological activities. In this review, we summarized the research progress on triterpenoids and their glycosides in Xanthoceras sorbifolia, including the chemical constituents, pharmacological activities, and biogenic pathways of triterpenoid mother nucleus. The results would provide a reference for further research and development of triterpenoids and their glycosides in Xanthoceras sorbifolia.

Recent Advances in the Nutritional Value, Chemical Compositions, Pharmacological Activity, and Application Value of Orychophragmus violaceus: A Comprehensive Review.

Orychophragmus violaceus (L.) O. E. Schulz (Brassicaceae) is widely distributed and plentiful in China and has been widely used for its application in ornamental, oil, ecology, foraging, and food. Recent studies have revealed that the main components of Orychophragmus violaceus include flavonoids, alkaloids, phenylpropanoids, phenolic acids, terpenoids, etc., which have pharmacological activities such as antioxidation, antiradiation, antitumor, hepatic protection, antiferroptosis, anti-inflammatory, and antibacterial. In this paper, the nutritional value, chemical compositions, pharmacological activity, and application value of Orychophragmus violaceus are summarized by referring to the relevant domestic and international literature to provide a reference for further research, development, and utilization of Orychophragmus violaceus in the future.

Highly Efficient Hemostatic Cross-Linked Polyacrylate Polymer Dressings for Immediate Hemostasis.

A traumatic hemorrhage is fatal due to the great loss of blood in a short period of time; however, there are a few biomaterials that can stop the bleeding quickly due to the limited water absorption speed. Here, a highly absorbent polymer (HPA), polyacrylate, was prepared as it has the best structure-effectiveness relationship. Within a very short period of time (2 min), HPA continually absorbed water until it swelled up to its 600 times its weight; more importantly, the porous structure comprised the swollen dressing. This instantaneous swelling immediately led to rapid hemostasis in irregular wounds. We optimized the HPA preparation process to obtain a rapidly water-absorbent polymer (i.e., HPA-5). HPA-5 showed favorable adhesion and biocompatibility in vitro. A rat femoral arteriovenous complete shear model and a tail arteriovenous injury model were established. HPA exhibited excellent hemostatic capability with little blood loss and short hemostatic time compared with CeloxTM in both of the models. The hemostatic mechanisms of HPA consist of fast clotting by aggregating blood cells, activating platelets, and accelerating the coagulation pathway via water absorption and electrostatic interaction. HPA is a promising highly water-absorbent hemostatic dressing for rapid and extensive blood clotting after vessel injury.

Design and Synthesis of 3-(2H-Chromen-3-yl)-5-aryl-1,2,4-oxadiazole Derivatives as Novel Toll-like Receptor 2/1 Agonists That Inhibit Lung Cancer In Vitro and In Vivo.

Toll-like receptor (TLR) 2 is a transmembrane receptor that participates in the innate immune response by forming a heterodimer with TLR1 or TLR6. TLR2 agonists play an important role in tumor therapy. Herein, we synthesized a series of 3-(2H-chromen-3-yl)-5-aryl-1,2,4-oxadiazole derivatives and identified WYJ-2 as a potent small and selective molecule agonist of TLR2/1, with an EC50 of 18.57 ± 0.98 nM in human TLR2 and TLR1 transient-cotransfected HEK 293T cells. WYJ-2 promoted the formation of TLR2/1 heterodimers and activated the nuclear factor kappa B (NF-κB) signaling pathway. Moreover, our study indicated that WYJ-2 could induce pyroptosis in cancer cells, mediated by activating the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. WYJ-2 exhibited effective anti-non-small cell lung cancer (NSCLC) activity in vitro and in vivo. The discovery that activating TLR2/1 induces pyroptosis in cancer cells may highlight the prospects of TLR2/1 agonists in cancer treatment in the future.

Design, synthesis, biological evaluation and in silico studies of novel quinoline derivatives as potential radioprotective molecules targeting the TLR2 and p53 pathways.

Ionizing radiation in space, radiation devices or nuclear disasters are major threats to human health and public security. In this paper, in order to find the potential novel compounds decreasing the radiation-induced damage by targeting p53 apoptosis pathway and TLR2 passway, a series of novel quinoline derivatives were designed, synthesized, and evaluated their biological activities. Most of the synthesized compounds showed significant radioprotective effects in vitro, and the compound 5 has the best performance. Therefore, we verified its radioprotective activity in vivo and investigated the mechanism of its excellent activity. The results in vivo indicated that compound 5 not only markedly enhanced the survival rate (80 %) of mice 30 days after lethal exposure to irradiation, but also significantly reduced the radiation-induced damage to haematopoietic system and intestinal tissue of mice. The mechanistic studies indicated that compound 5 acted on the p53 pathway to reduce radiation-induced cell apoptosis and at the same time stimulated TLR2 to up-regulate the expressions of radiation protection factors. Molecular dynamics study shows that compound 5 would effectively bind to the TLR2 protein and further revealed the binding mechanism. Taken together, all the findings of our study demonstrate the quinoline derivative 5 is a potent radioprotective compound, which holds a great therapeutic potential for further development.

Establishing efficient toluene elimination over cobalt-manganese bimetallic oxides via constructing strong Co-Mn interaction.

Doping proves to be an efficacious method of establishing intermetallic interactions for enhancing toluene oxidation performance of bimetallic oxides. However, conventional bimetallic oxide catalysts are yet to overcome their inadequacy in establishing intermetallic interactions. In this work, the dispersion of Mn-Co bimetallic sites was improved by hydrolytic co-precipitation, strengthening the intermetallic interactions which improved the structural and physicochemical properties of the catalysts, thus significantly enhancing its catalytic behavior. MnCo-H catalysts fabricated by the hydrolytic co-precipitation method showed promising catalytic performance (T50 = 223 °C, T90 = 229 °C), robust stability (at least 100 h) and impressive water resistance (under 10 vol.% of water) for toluene elimination. Hydrolytic co-precipitation has been found to improve dispersion of MnCo elements and to enhance interaction between Co and Mn ions (Mn4+ + Co2+ = Mn3+ + Co3+), resulting in a lower reduction temperature (215 °C) and a weaker Mn-O bond strength, creating more lattice defects and oxygen vacancies, which are responsible for superior catalytic properties of MnCo-H samples. Furthermore, in situ DRIFTs showed that gaseous toluene molecules adsorbed on the surface of MnCo-H were continuously oxidized to benzyl alcohol → benzaldehyde → benzoate, followed by a ring-opening reaction with surface-activated oxygen to convert to maleic anhydride as the final intermediate, which further generates water and carbon dioxide. It was also revealed that the ring-opening reaction for the conversion of benzoic acid to maleic anhydride is the rate-controlling step. This study reveals that optimizing active sites and improving reactive oxygen species by altering the dispersion of bimetals to enhance bimetallic interactions is an effective strategy for the improvement of catalytic behavior, while the hydrolytic co-precipitation method fits well with this corollary.

Glycosaminoglycans: Participants in Microvascular Coagulation of Sepsis.

Sepsis represents a syndromic response to infection and frequently acts as a common pathway leading to fatality in the context of various infectious diseases globally. The pathology of severe sepsis is marked by an excess of inflammation and activated coagulation. A substantial contributor to mortality in sepsis patients is widespread microvascular thrombosis-induced organ dysfunction. Multiple lines of evidence support the notion that sepsis induces endothelial damage, leading to the release of glycosaminoglycans, potentially causing microvascular dysfunction. This review aims to initially elucidate the relationship among endothelial damage, excessive inflammation, and thrombosis in sepsis. Following this, we present a summary of the involvement of glycosaminoglycans in coagulation, elucidating interactions among glycosaminoglycans, platelets, and inflammatory cells. In this section, we also introduce a reasoned generalization of potential signal pathways wherein glycosaminoglycans play a role in clotting. Finally, we discuss current methods for detecting microvascular conditions in sepsis patients from the perspective of glycosaminoglycans. In conclusion, it is imperative to pay closer attention to the role of glycosaminoglycans in the mechanism of microvascular thrombosis in sepsis. Dynamically assessing glycosaminoglycan levels in patients may aid in predicting microvascular conditions, enabling the monitoring of disease progression, adjustment of clinical treatment schemes, and mitigation of both acute and long-term adverse outcomes associated with sepsis.

Immune-Related Molecules CD3G and FERMT3: Novel Biomarkers Associated with Sepsis.

Sepsis ranks among the most common health problems worldwide, characterized by organ dysfunction resulting from infection. Excessive inflammatory responses, cytokine storms, and immune-induced microthrombosis are pivotal factors influencing the progression of sepsis. Our objective was to identify novel immune-related hub genes for sepsis through bioinformatic analysis, subsequently validating their specificity and potential as diagnostic and prognostic biomarkers in an animal experiment involving a sepsis mice model. Gene expression profiles of healthy controls and patients with sepsis were obtained from the Gene Expression Omnibus (GEO) and analysis of differentially expressed genes (DEGs) was conducted. Subsequently, weighted gene co-expression network analysis (WGCNA) was used to analyze genes within crucial modules. The functional annotated DEGs which related to the immune signal pathways were used for constructing protein-protein interaction (PPI) analysis. Following this, two hub genes, FERMT3 and CD3G, were identified through correlation analyses associated with sequential organ failure assessment (SOFA) scores. These two hub genes were associated with cell adhesion, migration, thrombosis, and T-cell activation. Furthermore, immune infiltration analysis was conducted to investigate the inflammation microenvironment influenced by the hub genes. The efficacy and specificity of the two hub genes were validated through a mice sepsis model study. Concurrently, we observed a significant negative correlation between the expression of CD3G and IL-1ß and GRO/KC. These findings suggest that these two genes probably play important roles in the pathogenesis and progression of sepsis, presenting the potential to serve as more stable biomarkers for sepsis diagnosis and prognosis, deserving further study.

Preclinical Pharmacokinetics and Biodistribution of LR004, a Novel Antiepidermal Growth Factor Receptor Monoclonal Antibody.

LR004 is a novel chimeric (human/mouse) monoclonal antibody developed for the treatment of advanced colorectal carcinoma with detectable epidermal growth factor receptor (EGFR) expression. We aimed to investigate the preclinical pharmacokinetics (PK) and in vivo biodistribution of LR004. The PK profiles of LR004 were initially established in rhesus monkeys. Subsequently, 125I radionuclide-labeled LR004 was developed and the biodistribution, autoradiography, and NanoSPECT/CT of 125I-LR004 in xenograft mice bearing A431 tumors were examined. The PK data revealed a prolonged half-life and nonlinear PK characteristics of LR004 within the dose range of 6-54 mg/kg. The radiochemical purity of 125I-LR004 was approximately 98.54%, and iodination of LR004 did not affect its specific binding activity to the EGFR antigen. In a classical biodistribution study, 125I-LR004 exhibited higher uptake in highly perfused organs than in poorly perfused organs. Prolonged retention properties of 125I-LR004 in tumors were observed at 4 and 10 days. Autoradiography and NanoSPECT/CT confirmed the sustained retention of 125I-LR004 at the tumor site in xenograft mice. These findings demonstrated the adequate tumor targeting capabilities of 125I-LR004 in EGFR-positive tumors, which may improve dosing strategies and future drug development.