Enhanced protein-metabolite correlation analysis: To investigate the association between Staphylococcus aureus mastitis and metabolic immune pathways.

Mastitis is a disease characterized by congestion, swelling, and inflammation of the mammary gland and usually caused by infection with pathogenic microorganisms. Furthermore, the development of mastitis is closely linked to the exogenous pathway of the gastrointestinal tract. However, the regulatory mechanisms governing the gut-metabolism-mammary axis remain incompletely understood. The present study revealed alterations in the gut microbiota of mastitis rats characterized by an increased abundance of the Proteobacteria phylum. Plasma analysis revealed significantly higher levels of L-isoleucine and cholic acid along with 7-ketodeoxycholic acid. Mammary tissue showed elevated levels of arachidonic acid metabolites and norlithocholic acid. Proteomic analysis showed increased levels of IFIH1, Tnfaip8l2, IRGM, and IRF5 in mastitis rats, which suggests that mastitis triggers an inflammatory response and immune stress. Follistatin (Fst) and progesterone receptor (Pgr) were significantly downregulated, raising the risk of breast cancer. Extracellular matrix (ECM) receptors and focal adhesion signaling pathways were downregulated, while blood-milk barrier integrity was disrupted. Analysis of protein-metabolic network regulation revealed that necroptosis, protein digestion and absorption, and arachidonic acid metabolism were the principal regulatory pathways involved in the development of mastitis. In short, the onset of mastitis leads to changes in the microbiota and alterations in the metabolic profiles of various biological samples, including colonic contents, plasma, and mammary tissue. Key manifestations include disturbances in bile acid metabolism, amino acid metabolism, and arachidonic acid metabolism. At the same time, the integrity of the blood-milk barrier is compromised while inflammation is promoted, thereby reducing cell adhesion in the mammary glands. These findings contribute to a more comprehensive understanding of the metabolic status of mastitis and provide new insights into its impact on the immune system.

The Potential Mechanism of Liujunzi Decoction in the Treatment of Breast Cancer Based on Network Pharmacology and Molecular Docking Technology.

BACKGROUND: Liujunzi Decoction (LJZD) is a potential clinical treatment for Breast Cancer (BC), but the active ingredients and mechanisms underlying its effectiveness remain unclear. OBJECTIVE: The study aimed to investigate the target gene of LJZD compatibility and the possible mechanism of action in the treatment of breast cancer by using network pharmacology and molecular docking. METHODS: Based on TCMSP, ETCM, and BATMAN database searching and screening to obtain the ingredients of LJZD, the related targets were obtained. Breast cancer-related targets were collected through GEO, Geencards, OMIM, and other databases, and drug-disease Venn diagrams were drawn by R. The PPI network map was constructed by using Cytoscape. The intersecting targets were imported into the STRING database, and the core targets were analyzed and screened. The intersected targets were analyzed by the DAVID database for GO and KEGG enrichment. AutoDock Vina and Gromacs were used for molecular docking and simulation of the core targets and active ingredients. RESULTS: 126 active ingredients of LJZD were obtained; 241 targets related to breast cancer were sought after screening, and 180 intersection targets were identified through Venn diagram analysis. The core targets were FOS and ESR1. KEGG enrichment analysis mainly involved PI3K/Akt, MAPK, and other signaling pathways. CONCLUSION: This study has explored the possible targets and signaling pathways of LJZD in treating breast cancer through network pharmacology and bioinformatics analysis. Molecular docking and simulation have further validated the potential mechanism of action of LJZD in breast cancer treatment, providing essential experimental data for future studies.

Structural analysis of polysaccharide from Inonotus obliquus and investigate combined impact on the sex hormones, intestinal microbiota and metabolism in SPF male mice.

The dysregulation of sex hormone levels is associated with metabolic disorders such as obesity. Inonotus obliquus polysaccharide (IOP) exhibits a promising therapeutic effect on conditions like obesity and diabetes, potentially linked to its influence on intestinal microbiota and metabolism. The exact cause and mechanisms that link sex hormones, gut microbiota and metabolism are still unknown. In this research, we examined the molecular weight, monosaccharide composition, and glycosidic bond type of IOP. We found that IOP mostly consists of alpha-structured 6­carbon glucopyranose, with a predominant (1 â†’ 4) linkage to monosaccharides and a uniform distribution. Following this, we administered two different concentrations of IOP to mice through gavage. The results of the enzyme-linked immunosorbent assay (ELISA) demonstrated a significant increase in testosterone (T) levels in the IOP group as compared to the control group. Additionally, the results of tissue immunofluorescence indicated that increased IOP led to a decrease in adiponectin content and an increase in SET protein expression. The study also revealed changes in the intestinal microbiota and metabolic changes in mice through 16S rRNA data and non-targeted LC-MS data, respectively. The study also found that IOP mainly affects pathways linked to glycerophospholipid metabolism. In addition, it has been observed that there is an increase in the number of beneficial bacteria, such as the Eubacterium coprostanoligenes group and g.Lachnospiraceae NK4A136 group, while the levels of metabolites that are linked to obesity or diabetes, such as 1,5-anhydrosorbitol, are reduced. Furthermore, biomarker screening has revealed that the main microorganism responsible for the differences between the three groups is g.Erysipelatoclostridiaceae. In summary, these findings suggest that IOP exerts its therapeutic effects through a synergistic interplay between sex hormones, gut microbiome composition, and metabolic processes.

Drug-Induced Acute Pancreatitis: A Real-World Pharmacovigilance Study Using the FDA Adverse Event Reporting System Database.

Timely identification and discontinuation of culprit-drug is the cornerstone of clinical management of drug-induced acute pancreatitis (AP), but the comprehensive landscape of AP culprit-drugs is still lacking. To provide the current overview of AP culprit-drugs to guide clinical practice, we reviewed the adverse event (AE) reports associated with AP in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database from 2004 to 2022, and summarized a potential AP culprit-drug list and its corresponding AE report quantity proportion. The disproportionality analysis was used to detect adverse drug reaction (ADR) signals for each drug in the drug list, and the ADR signal distribution was integrated to show the risk characteristic of drugs according to the ADR signal detection results. In the FAERS database, a total of 62,206 AE reports were AP-related, in which 1,175 drugs were reported as culprit-drug. On the whole, metformin was the drug with the greatest number of AE reports, followed by quetiapine, liraglutide, exenatide, and sitagliptin. Drugs used in diabetes was the drug class with the greatest number of AE reports, followed by immunosuppressants, psycholeptics, drugs for acid-related disorders, and analgesics. In disproportionality analysis, 595 drugs showed potential AP risk, whereas 580 drugs did not show any positive ADR signal. According to the positive-negative distribution of the ADR signal for drug classes, the drug class with the greatest number of positive drugs was antineoplastic agents. In this study, we provided the current comprehensive landscape of AP culprit-drugs from the pharmacovigilance perspective, which can provide reference information for clinical practice.

Inonotus obliquus polysaccharide are linear molecules that alter the abundance and composition of intestinal microbiota in Sprague Dawley rats.

Introduction: The macromolecular polysaccharide Inonotus obliquus polysaccharide (IOP) is composed of various monosaccharides, and it could modulate the composition and diversity of intestinal flora. However, its impact on the intestinal flora in rats of different genders remains unclear. Therefore, this study aims to investigate the structural changes of IOP and its effects on the intestinal flora after administration in male and female rats. Methods: In this study, the molecular weight and purity of IOP were analyzed by high-performance gel permeation chromatography (HPGPC) and phenol sulfuric acid method, and NMR was used to confirm the chemical structure of IOP. Sex hormone [testosterone (T) and estradiol (E2)] levels and intestinal microbial changes were detected by enzyme-linked immunosorbent assay (ELISA) and 16S rRNA, respectively, after gavage of IOP (100 mg/kg) in male and female Sprague Dawley (SD) rats. Results: HPGPC analysis showed that the average molecular weight (Mw) of IOP was 4,828 Da, and the total sugar content of the purified IOP was 96.2%, indicating that the polysaccharide is of high purity. NMR revealed that IOP is a linear macromolecule with an α-D-type glucose backbone. The results of ELISA and 16S rRNA showed that the IOP increased the abundance of beneficial bacteria, such as Clostridia_UCG-014 and Prevotellaceae_NK3B31, and reduced that of harmful bacteria, such as Colidextribacter and Desulfobacterota in the intestine of both male and female rats, and IOP changed the levels of sex hormones in male and female rats. Further analyses revealed that the increase in alpha diversity was higher in male than female rats. α diversity and ß diversity revealed a significant difference in the composition of cecal microbiota between male and female rats in the control group, but IOP intake reduced this difference. Meanwhile, α analysis revealed a change in the composition of bacterial flora was more stable in male than female rats. Conclusions: This study enhances our comprehension of the IOP structure and elucidates the alterations in intestinal flora following IOP administration in rats of varying genders. Nonetheless, further investigation is warranted to explore the specific underlying reasons for these discrepancies.

Chromosome-specific painting in Thinopyrum species using bulked oligonucleotides.

KEY MESSAGE: Chromosome-specific painting probes were developed to identify the individual chromosomes from 1 to 7E in Thinopyrum species and detect alien genetic material of the E genome in a wheat background. The E genome of Thinopyrum is closely related to the ABD genome of wheat (Triticum aestivum L.) and harbors genes conferring beneficial traits to wheat, including high yield, disease resistance, and unique end-use quality. Species of Thinopyrum vary from diploid (2n = 2x = 14) to decaploid (2n = 10x = 70), and chromosome structural variation and differentiation have arisen during polyploidization. To investigate the variation and evolution of the E genome, we developed a complete set of E genome-specific painting probes for identification of the individual chromosomes 1E to 7E based on the genome sequences of Th. elongatum (Host) D. R. Dewey and wheat. By using these new probes in oligonucleotide-based chromosome painting, we showed that Th. bessarabicum (PI 531711, EbEb) has a close genetic relationship with diploid Th. elongatum (EeEe), with five chromosomes (1E, 2E, 3E, 6E, and 7E) maintaining complete synteny in the two species except for a reciprocal translocation between 4 and 5Eb. All 14 pairs of chromosomes of tetraploid Th. elongatum have maintained complete synteny with those of diploid Th. elongatum (Thy14), but the two sets of E genomes have diverged. This study also demonstrated that the E genome-specific painting probes are useful for rapid and effective detection of the alien genetic material of E genome in wheat-Thinopyrum derived lines.

Environmental cadmium exposure alters the internal microbiota and metabolome of Sprague-Dawley rats.

Cadmium (Cd) is a toxic element that can negatively affect both humans and animals. It enters the human and animal bodies through the respiratory and digestive tracts, following which it tends to accumulate in different organs, thereby seriously affecting human and animal health, as well as hampering social and economic development. Cd exposure can alter the composition of intestinal microbiota. In addition, it can damage the peripheral organs by causing the translocation of intestinal microbiota. However, the relationship between translocation-induced changes in the composition of microbiome in the blood and metabolic changes remains unclear. In the present study, we investigated the effects of Cd exposure on microbiota and serum metabolism in rats by omics analysis. The results demonstrated that Cd exposure disrupted the balance between the blood and intestinal flora in Sprague-Dawley (SD) rats, with a significant increase in gut microbiota (Clostridia_UCG_014, NK4A214_group) and blood microbiome (Corynebacterium, Muribaculaceae). However, Cd exposure caused the translocation of Corynebacterium and Muribaculaceae from the gut into the blood. In addition, Cd exposure was associated with the up-regulation of serum indoxyl sulfate, phenyl sulfate, and p-cresol sulfate; down-regulation of δ-tocopherol and L-glutamine; and changes in blood microbiome and metabolites. In conclusion, we identified novel metabolic biomarkers for Cd toxicity, which will also expand our understanding of the role of blood microbiome in Cd-induced injury.

Procyanidin B2 alleviates uterine toxicity induced by cadmium exposure in rats: The effect of oxidative stress, inflammation, and gut microbiota.

Environmental exposure to hazardous materials causes enormous socioeconomic problems due to its deleterious impacts on human beings, agriculture and animal husbandry. As an important hazardous material, cadmium can promote uterine oxidative stress and inflammation, leading to reproductive toxicity. Antioxidants have been reported to attenuate the reproductive toxicity associated with cadmium exposure. In this study, we investigated the potential protective effect of procyanidin oligosaccharide B2 (PC-B2) and gut microbiota on uterine toxicity induced by cadmium exposure in rats. The results showed that the expression levels of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were reduced in utero. Proinflammatory cytokines (including tumor necrosis factor-α, interleukin-1ß and interleukin-6), the NLRP3 inflammasome, Caspase-1 and pro-IL-1ß were all involved in inflammatory-mediated uterine injury. PC-B2 prevented CdCl2-induced oxidative stress and inflammation in uterine tissue by increasing antioxidant enzymes and reducing proinflammatory cytokines. Additionally, PC-B2 significantly reduced cadmium deposition in the uterus, possibly through its significant increase in MT1, MT2, and MT3 mRNA expression. Interestingly, PC-B2 protected the uterus from CdCl2 damage by increasing the abundance of intestinal microbiota, promoting beneficial microbiota, and inhibiting harmful microbiota. This study provides novel mechanistic insights into the toxicity of environmental cadmium exposure and indicates that PC-B2 could be used in the prevention of cadmium exposure-induced uterine toxicity.

Real-World Data in Pharmacovigilance Database Provides a New Perspective for Understanding the Risk of Clostridium difficile Infection Associated with Antibacterial Drug Exposure.

Antibacterial drug exposure (ADE) is a well-known potential risk factor for Clostridium difficile infection (CDI), but it remains controversial which certain antibacterial drugs are associated with the highest risk of CDI occurrence. To summarize CDI risk associated with ADE, we reviewed the CDI reports related to ADE in the FDA Adverse Event Reporting System database and conducted disproportionality analysis to detect adverse reaction (ADR) signals of CDI for antibacterial drugs. A total of 8063 CDI reports associated with ADE were identified, which involved 73 antibacterial drugs. Metronidazole was the drug with the greatest number of reports, followed by vancomycin, ciprofloxacin, clindamycin and amoxicillin. In disproportionality analysis, metronidazole had the highest positive ADR signal strength, followed by vancomycin, cefpodoxime, ertapenem and clindamycin. Among the 73 antibacterial drugs, 58 showed at least one positive ADR signal, and ceftriaxone was the drug with the highest total number of positive signals. Our study provided a real-world overview of CDI risk for AED from a pharmacovigilance perspective and showed risk characteristics for different antibacterial drugs by integrating its positive-negative signal distribution. Meanwhile, our study showed that the CDI risk of metronidazole and vancomycin may be underestimated, and it deserves further attention and investigation.

Corrigendum: Combined intestinal metabolomics and microbiota analysis for acute endometritis induced by lipopolysaccharide in mice.

[This corrects the article DOI: 10.3389/fcimb.2021.791373.].

Severe cutaneous adverse reactions to drugs: A real-world pharmacovigilance study using the FDA Adverse Event Reporting System database.

Background: Sound drug safety information is important to optimize patient management, but the widely recognized comprehensive landscape of culprit-drugs that cause severe cutaneous adverse reactions (SCARs) is currently lacking. Objective: The main aim of the study is to provide a comprehensive landscape of culprit-drugs for SCARs to guide clinical practice. Methods: We analyzed reports associated with SCARs in the FDA Adverse Event Reporting System database between 1 January 2004 and 31 December 2021 and compiled a list of drugs with potentially serious skin toxicity. According to this list, we summarized the reporting proportions of different drugs and drug classes and conducted disproportionality analysis for all the drugs. In addition, the risk characteristic of SCARs due to different drugs and drug classes was summarized by the positive-negative distribution based on the results of the disproportionality analysis. Results: A total of 77,789 reports in the FDA Adverse Event Reporting System database were considered SCAR-related, of which lamotrigine (6.2%) was the most reported single drug followed by acetaminophen (5.8%) and allopurinol (5.8%) and antibacterials (20.6%) was the most reported drug class followed by antiepileptics (16.7%) and antineoplastics (11.3%). A total of 1,219 drugs were reported as culprit-drugs causing SCARs in those reports, and the largest number of drugs belonged to antineoplastics. In disproportionality analysis, 776 drugs showed at least one positive pharmacovigilance signal. Drugs with the most positive signals were lamotrigine, acetaminophen, furosemide, and sulfamethoxazole/trimethoprim. Conclusion: Our study provided a real-world overview of SCARs to drugs, and the investigation of SCAR positive-negative distribution across different drugs revealed its risk characteristics, which may help optimize patient management.

The impact of pharmacist early active consultation (PEAC) on multidrug resistance organism treatment outcomes: A prospective historically controlled study.

Background and aim: Infectious disease (ID) consultation can improve multidrug-resistant organism (MDRO) treatment outcomes. However, the impact of clinical pharmacists' ID consultation on MDRO therapy, especially early initiation, has not been reported. In this study, we try to explore the impact of the pharmacist early active consultation (PEAC) on MDRO patient management. Methods: We conducted a prospective historical controlled study based on PEAC in MDRO patients. The retrospective control group was patients hospitalized 18 months before the PEAC initiation, and the prospective PEAC group was patients hospitalized 18 months after the PEAC initiation. Primary endpoint was 30-day all-cause mortality. Secondary outcomes were MDRO clinical outcome, duration of antibiotic use, length of stay, antibiotic consumption and antibiotic costs. Further subgroup analysis of secondary outcomes was performed by the condition at admission, MDRO pathogenicity and MDRO clinical outcome. Results: 188 MDRO patients were included. After adjusting for potential predictors, PEAC reduced the 30-day all-cause mortality by 70% (HR 0.30, 95% CI 0.09-0.96, p = 0.042). PEAC group had clinical improvement than control group (89.47% vs. 65.59%, p < 0.001), especially in patients with non-severe clinical conditions at admission (98.41% vs. 70.18%, p < 0.001). However, no significant differences were found between groups in length of stay, antibiotics consumption, and antibiotics costs. Conclusion: Early active pharmacy ID consultation can reduce 30-day all-cause mortality and improve clinical outcomes in MDRO patients.

Molecular basis of RADAR anti-phage supramolecular assemblies.

Adenosine-to-inosine RNA editing has been proposed to be involved in a bacterial anti-phage defense system called RADAR. RADAR contains an adenosine triphosphatase (RdrA) and an adenosine deaminase (RdrB). Here, we report cryo-EM structures of RdrA, RdrB, and currently identified RdrA-RdrB complexes in the presence or absence of RNA and ATP. RdrB assembles into a dodecameric cage with catalytic pockets facing outward, while RdrA adopts both autoinhibited tetradecameric and activation-competent heptameric rings. Structural and functional data suggest a model in which RNA is loaded through the bottom section of the RdrA ring and translocated along its inner channel, a process likely coupled with ATP-binding status. Intriguingly, up to twelve RdrA rings can dock one RdrB cage with precise alignments between deaminase catalytic pockets and RNA-translocation channels, indicative of enzymatic coupling of RNA translocation and deamination. Our data uncover an interesting mechanism of enzymatic coupling and anti-phage defense through supramolecular assemblies.

Evidence-based guideline for the prevention and management of perioperative infection.

BACKGROUND: We have updated the guideline for preventing and managing perioperative infection in China, given the global issues with antimicrobial resistance and the need to optimize antimicrobial usage and improve hospital infection control levels. METHODS: We conducted a comprehensive evaluation of the evidence for prevention and management of perioperative infection, based on the concepts of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The strength of recommendations was graded and voted using the Delphi method and the nominal group technique. Revisions were made to the guidelines in response to feedback from the experts. RESULTS: There were 17 questions prepared, for which 37 recommendations were made. According to the GRADE system, we evaluated the body of evidence for each clinical question. Based on the meta-analysis results, recommendations were graded using the Delphi method to generate useful information. CONCLUSIONS: This guideline provides evidence to perioperative antimicrobial prophylaxis that increased the rational use of prophylactic antimicrobial use, with substantial improvement in the risk-benefit trade-off.

Drug-induced QT prolongation and torsade de pointes: a real-world pharmacovigilance study using the FDA Adverse Event Reporting System database.

Introduction: Drug-induced QT prolongation and (or) Torsade de Pointes (TdP) is a well-known serious adverse reaction (ADR) for some drugs, but the widely recognized comprehensive landscape of culprit-drug of QT prolongation and TdP is currently lacking. Aim: To identify the top drugs reported in association with QT prolongation and TdP and provide information for clinical practice. Method: We reviewed the reports related to QT prolongation and TdP in the FDA Adverse Event Reporting System (FAERS) database from January 1, 2004 to December 31, 2022, and summarized a potential causative drug list accordingly. Based on this drug list, the most frequently reported causative drugs and drug classes of QT prolongation and TdP were counted, and the disproportionality analysis for all the drugs was conducted to in detect ADR signal. Furthermore, according to the positive-negative distribution of ADR signal, we integrated the risk characteristic of QT prolongation and TdP in different drugs and drug class. Results: A total of 42,713 reports in FAERS database were considered to be associated with QT prolongation and TdP from 2004 to 2022, in which 1,088 drugs were reported as potential culprit-drugs, and the largest number of drugs belonged to antineoplastics. On the whole, furosemide was the most frequently reported drugs followed by acetylsalicylic acid, quetiapine, citalopram, metoprolol. In terms of drug classes, psycholeptics was the most frequently reported drug classes followed by psychoanaleptics, analgesics, beta blocking agents, drugs for acid related disorders. In disproportionality analysis, 612 drugs showed at least one positive ADR signals, while citalopram, ondansetron, escitalopram, loperamide, and promethazine were the drug with the maximum number of positive ADR signals. However, the positive-negative distribution of ADR signals between different drug classes showed great differences, representing the overall risk difference of different drug classes. Conclusion: Our study provided a real-world overview of QT prolongation and TdP to drugs, and the presentation of the potential culprit-drug list, the proportion of reports, the detection results of ADR signals, and the distribution characteristics of ADR signals may help understand the safety profile of drugs and optimize clinical practice.

Managingtomato bacterial wilt by suppressing Ralstonia solanacearum population in soil and enhancing host resistance through fungus-derived furoic acid compound.

Synthetic chemical pesticides are primarily used to manage plant pests and diseases, but their widespread and unregulated use has resulted in major health and environmental hazards. Using biocontrol microbes and their bioactive compounds is a safe and sustainable approach in plant protection. In this study, a furoic acid (FA) compound having strong antibacterial activity against soil-borne phytopathogenic bacterium Ralstonia solanacearum [causal agent of bacterial wilt (BW) disease] was isolated from Aspergillus niger and identified as 5-(hydroxymethyl)-2-furoic acid compound through spectroscopic analyses (liquid chromatography-mass spectrometry (MS), electron ionization MS, and NMR). The SEM study of bacterial cells indicated the severe morphological destructions by the FA compound. The FA was further evaluated to check its potential in enhancing host resistance and managing tomato BW disease in a greenhouse experiment and field tests. The results showed that FA significantly enhanced the expression of resistance-related genes (PAL, LOX, PR1, and PR2) in tomato and caused a significant reduction (11.2 log10 colony-forming units/g) of the R. solanacearum population in soil, resulting in the reduction of bacterial wilt disease severity on tomato plants and increase in plant length (58 ± 2.7 cm), plant biomass (28 ± 1.7 g), and root length (13 ± 1.2 cm). The findings of this study suggested that the fungus-derived FA compound can be a potential natural compound of biological source for the soil-borne BW disease in tomato.

Polysaccharide derived from Inonotus obliquus inhibits lipopolysaccharide-induced acute endometritis in mice.

OBJECTIVE: Endometritis bacterial pathogenic condition that affects both humans and animals develops in the inner lining of the uterus. Inonotus obliquus polysaccharide (IOP), an active cocktail of Inonotus obliquus, has been shown to have a relatively wide range of biological activities and can play a role in various diseases. However, from the currently reported article, there is no information about the anti-inflammatory effect of IPO in the symptoms of lipopolysaccharide (LPS)-induced endometritis. Therefore, this study carefully observed the phenomenon of IOP on the symptoms of endometritis induced by LPS in mice, elucidated the protective mechanism of IOP on the body, and clarified the potential mechanism of IOP. METHODS: A total of 72 BALB/c female experimental mice were divided into several groups for comparison. They were the blank control group, the LPS group, the LPS+ IOP group (the effect of IOP dose on mice was also explored, divided into low, medium, and high) and LPS+ amoxicillin group. All groups except control group were infused with LPS into the uterus. The mice of LPS+ IOP groups and LPS+ amoxicillin group were orally administered with IOP or amoxicillin after LPS challenge for 3 hours. Histopathology and myeloperoxidase (MPO) activity were used to detect uterine tissue injury, and cytokine levels were used to measure uterine inflammation. The expression of toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB)-related proteins in the inflammatory signaling pathway was observed. RESULTS: Pathological and MPO activity analyses revealed that IOP relieved LPS-induced uterine tissue injury. Quantitative reverse transcription-polymerase chain reaction was used to detect and quantitatively study the RNA information of mouse cells, which had high accuracy and sensitivity. From the test results, IOP does effectively control the release of pro-inflammatory cytokines such as interleukin-6 (IL-6), IL-1ß, IL-8 and tumor necrosis factor-α (TNF-α), avoiding the body's immune response. Analysis of uterine tissue cell components also confirmed that the expression level of inflammatory mediator-induced nitric oxide synthase (iNOS) was also greatly reduced. Analysis of western blotting results of cell synthesis showed that IOP mainly inhibited the protein expression of TLR4 and myeloid differentiation factor 88 in the body. CONCLUSION: This study proved that the mechanism of action of IOP is to inhibit the TLR4/NF-κB signaling pathway to reduce the release of pro-inflammatory cytokines from body cells, thereby alleviating the symptoms of endometritis induced by LPS. Thus, IOP may act as an effective drug in preventing and curing LPS-induced endometritis.

PD-1 inhibitor-based adverse events in solid tumors: A retrospective real-world study.

Background & Aims: Immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer treatment, and ICI-related toxicities (i.e., immune-related adverse events (irAEs) have been reported in many clinical studies. However, the toxicity data of real-world have not been fully assessed. Methods: Patients with histologically confirmed solid tumors who had been treated with PD-1 inhibitors were included in the study. Patient data were collected from electronic medical records, including basic characteristics, data of irAEs, management and outcome. Incidences of irAEs were pooled and compared, and the risk of irAEs was also analyzed. Results: A total of 362 solid tumor patients treated with sintilimab (n = 171), camrelizumab (n = 60), toripalimab (n = 72), and pembrolizumab (n = 59) were included. In total, any grade irAEs, grade 1-2 irAEs, and grade ≥3 irAEs accounted for 47.24%, 38.67% and 8.56% of cases, reapectively. Further, 29.24% of patients discontinued immunotherapy due to irAEs, with pneumonitis being the main reason for discontinuation. By comparing the toxicity profiles between different ICIs, we found that reactive capillary haemangiomas were camrelizumab-specific. Additionally, the frequency of irAEs was association with ICIs type, the pooled incidence (standardized rate) of irAEs related to sintilimab, camrelizumab, toripalimab and pembrolizumab were 55.56% (52.81%), 48.33% (55.55%), 33.33% (29.23%) and 38.98% (38.29%), respectively. Sintilimab and camrelizumab had higher incidences of any grade and grade 1-2 than toripalimab (55.56% vs. 33.33%, p = 0.002; 48.54% vs. 25.00%, p = 0.0001) and pembrolizumab (55.56% vs. 38.98%, p = 0.0028; 48.54% vs. 25.42%, p = 0.002), while the grade ≥3 irAEs of pembrolizumab (13.56%) were approximately 1.63- to 1.93-fold higher than other ICIs, and the standardized grade ≥3 of pembrolizumab was significantly higher than that of sintilimab (13.21% vs. 7.12%, p = 0.026), especially for grade ≥3 pneumonitis. Multivariate analysis found that cumulative cycles of ICI (OR = 1.081; 95% CI: 1.023-1.142; p = 0.006), and lung cancer (OR = 1.765; 95% CI: 1.105-2.820; p = 0.017) were independent risk factors for irAEs. Conclusion: The frequency of irAEs is associated with ICI type. The pooled incidence of irAEs related to sintilimab and pneumonitis caused by pembrolizumab were higher. These data indicate the importance of having different monitoring priorities for different PD-1 inhibitors.

Asparaginase-related diabetic ketoacidosis: Analysis of the FDA Adverse Event Reporting System (FAERS) data and literature review.

WHAT IS KNOWN AND OBJECTIVE: Diabetic ketoacidosis (DKA) may occur during asparaginase use. However, limited by the study population, the association between asparaginase and DKA has not been elucidated. The purpose of this study was to determine the potential association between asparaginase and DKA and analyse related clinical characteristics and possible risk factor. METHODS: Disproportionality analysis with the reporting odd ratio (ROR) was used to detect the adverse reaction signals of asparaginase-associated DKA in Food and Drug Administration Adverse Event Reporting System (FAERS). A literature review was conducted to further analyse clinical characteristics, possible risk factor and something noteworthy in asparaginase-associated DKA. RESULTS AND DISCUSSION: A total of 12 reports of DKA associated with l-asparaginase (l-asp) and 6 reports associated with pegaspargase (PEG-asp) were extracted in FAERS, more than 50% of the cases were classified as serious adverse events. DKA was a positive signal of l-asp (ROR = 2.397, 95% CI 1.360-4.226), while not closely related to the use of PEG-asp (ROR = 1.602, 95% CI 0.719-3.570). Searched in PubMed, Embase and Web of Science, a total of eight patients were collected. The patients were mainly adolescent patients, aged between 11 and 25 years old with a median age of 16 years. Drug dosage form distribution is unbalanced, 7 patients received l-asp and only 1 received PEG-asp. WHAT IS NEW AND CONCLUSIONS: The ROR of KDA caused by l-asp was statistically significant, but there was not a statistical association for DKA caused by PEG-asp. Asparaginase dosage form may affect the occurrence of DKA, but further research is needed.

Recognition of cyclic dinucleotides and folates by human SLC19A1.

Cyclic dinucleotides (CDNs) are ubiquitous signalling molecules in all domains of life1,2. Mammalian cells produce one CDN, 2'3'-cGAMP, through cyclic GMP-AMP synthase after detecting cytosolic DNA signals3-7. 2'3'-cGAMP, as well as bacterial and synthetic CDN analogues, can act as second messengers to activate stimulator of interferon genes (STING) and elicit broad downstream responses8-21. Extracellular CDNs must traverse the cell membrane to activate STING, a process that is dependent on the solute carrier SLC19A122,23. Moreover, SLC19A1 represents the major transporter for folate nutrients and antifolate therapeutics24,25, thereby placing SLC19A1 as a key factor in multiple physiological and pathological processes. How SLC19A1 recognizes and transports CDNs, folate and antifolate is unclear. Here we report cryo-electron microscopy structures of human SLC19A1 (hSLC19A1) in a substrate-free state and in complexes with multiple CDNs from different sources, a predominant natural folate and a new-generation antifolate drug. The structural and mutagenesis results demonstrate that hSLC19A1 uses unique yet divergent mechanisms to recognize CDN- and folate-type substrates. Two CDN molecules bind within the hSLC19A1 cavity as a compact dual-molecule unit, whereas folate and antifolate bind as a monomer and occupy a distinct pocket of the cavity. Moreover, the structures enable accurate mapping and potential mechanistic interpretation of hSLC19A1 with loss-of-activity and disease-related mutations. Our research provides a framework for understanding the mechanism of SLC19-family transporters and is a foundation for the development of potential therapeutics.