Genetic analysis of seven patients with inherited ichthyosis and Nagashima­type palmoplantar keratoderma.

Inherited ichthyosis comprises a series of heterogeneous dermal conditions; it mainly manifests as widespread hyperkeratosis, xerosis and scaling of the skin. At times, overlapping symptoms require differential diagnosis between ichthyosis and several other similar disorders. The present study reports seven patients with confirmed or suspected to be associated with ichthyosis by conducting a thorough clinical and genetic investigation. Genetic testing was conducted using whole­exome sequencing, with Sanger sequencing as the validation method. The MEGA7 program was used to analyze the conservation of amino acid residues affected by the detected missense variants. The enrolled patients exhibited ichthyosis­like but distinct clinical manifestations. Genetic analysis identified diagnostic variations in the FLG, STS, KRT10 and SERPINB7 genes and clarified the carrying status of each variant in the respective family members. The two residues affected by the detected missense variants remained conserved across multiple species. Of note, the two variants, namely STS: c.452C>T(p.P151L) and c.647_650del(p.L216fs) are novel. In conclusion, a clear genetic differential diagnosis was made for the enrolled ichthyosis­associated patients; the study findings also extended the mutation spectrum of ichthyosis and provided solid evidence for the counseling of the affected families.

Reliable detection of generalized convulsive seizures using an off-the-shelf digital watch: A multisite phase 2 study.

OBJECTIVE: The aim of this study was to develop a machine learning algorithm using an off-the-shelf digital watch, the Samsung watch (SM-R800), and evaluate its effectiveness for the detection of generalized convulsive seizures (GCS) in persons with epilepsy. METHODS: This multisite epilepsy monitoring unit (EMU) phase 2 study included 36 adult patients. Each patient wore a Samsung watch that contained accelerometer, gyroscope, and photoplethysmographic sensors. Sixty-eight time and frequency domain features were extracted from the sensor data and were used to train a random forest algorithm. A testing framework was developed that would better reflect the EMU setting, consisting of (1) leave-one-patient-out cross-validation (LOPO CV) on GCS patients, (2) false alarm rate (FAR) testing on nonseizure patients, and (3) "fixed-and-frozen" prospective testing on a prospective patient cohort. Balanced accuracy, precision, sensitivity, and FAR were used to quantify the performance of the algorithm. Seizure onsets and offsets were determined by using video-electroencephalographic (EEG) monitoring. Feature importance was calculated as the mean decrease in Gini impurity during the LOPO CV testing. RESULTS: LOPO CV results showed balanced accuracy of .93 (95% confidence interval [CI] = .8-.98), precision of .68 (95% CI = .46-.85), sensitivity of .87 (95% CI = .62-.96), and FAR of .21/24 h (interquartile range [IQR] = 0-.90). Testing the algorithm on patients without seizure resulted in an FAR of .28/24 h (IQR = 0-.61). During the "fixed-and-frozen" prospective testing, two patients had three GCS, which were detected by the algorithm, while generating an FAR of .25/24 h (IQR = 0-.89). Feature importance showed that heart rate-based features outperformed accelerometer/gyroscope-based features. SIGNIFICANCE: Commercially available wearable digital watches that reliably detect GCS, with minimum false alarm rates, may overcome usage adoption and other limitations of custom-built devices. Contingent on the outcomes of a prospective phase 3 study, such devices have the potential to provide non-EEG-based seizure surveillance and forecasting in the clinical setting.

Palladium-Catalyzed Intermolecular Dehydrogenative C-2 Pentenylation of Indoles with 2-Methyl-2-butene.

Five-carbon (C5) units are the fundamental building blocks that constitute a multitude of natural products. Herein we report an unprecedented unusual C5 functionalization of indole regioselectively at the C-2-position enabled by a (2-pyridyl)sulfonyl-directing palladium-catalyzed dehydrogenative strategy with a bulk chemical 2-methyl-2-butene as a C5 source. Compared to typical C5 functionalization using pentenyl alcohols, carbonates, borates, or halides as the C5 source, the protocol not only has a low cost advantage but also is of atom and step economy.

Non-traumatic osteonecrosis of the femoral head induced by steroid and alcohol exposure is associated with intestinal flora alterations and metabolomic profiles.

OBJECTIVE: Osteonecrosis of the femoral head (ONFH) is a severe disease that primarily affects the middle-aged population, imposing a significant economic and social burden. Recent research has linked the progression of non-traumatic osteonecrosis of the femoral head (NONFH) to the composition of the gut microbiota. Steroids and alcohol are considered major contributing factors. However, the relationship between NONFH caused by two etiologies and the microbiota remains unclear. In this study, we examined the gut microbiota and fecal metabolic phenotypes of two groups of patients, and analyzed potential differences in the pathogenic mechanisms from both the microbial and metabolic perspectives. METHODS: Utilizing fecal samples from 68 NONFH patients (32 steroid-induced, 36 alcohol-induced), high-throughput 16 S rDNA sequencing and liquid chromatography with tandem mass spectrometry (LC-MS/MS) metabolomics analyses were conducted. Univariate and multivariate analyses were applied to the omics data, employing linear discriminant analysis effect size to identify potential biomarkers. Additionally, functional annotation of differential metabolites and associated pathways was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Subsequently, Spearman correlation analysis was employed to assess the potential correlations between differential gut microbiota and metabolites. RESULTS: High-throughput 16 S rDNA sequencing revealed significant gut microbial differences. At the genus level, the alcohol group had higher Lactobacillus and Roseburia, while the steroid group had more Megasphaera and Akkermansia. LC-MS/MS metabolomic analysis indicates significant differences in fecal metabolites between steroid- and alcohol-induced ONFH patients. Alcohol-induced ONFH (AONFH) showed elevated levels of L-Lysine and Oxoglutaric acid, while steroid-induced ONFH(SONFH) had increased Gluconic acid and Phosphoric acid. KEGG annotation revealed 10 pathways with metabolite differences between AONFH and SONFH patients. Correlation analysis revealed the association between differential gut flora and differential metabolites. CONCLUSIONS: Our results suggest that hormones and alcohol can induce changes in the gut microbiota, leading to alterations in fecal metabolites. These changes, driven by different pathways, contribute to the progression of the disease. The study opens new research directions for understanding the pathogenic mechanisms of hormone- or alcohol-induced NONFH, suggesting that differentiated preventive and therapeutic approaches may be needed for NONFH caused by different triggers.

Long-distance transmission of arbitrary quantum states between spatially separated microwave cavities.

Long-distance transmission between spatially separated microwave cavities is a crucial area of quantum information science and technology. In this work, we present a method for achieving long-distance transmission of arbitrary quantum states between two microwave cavities, by using a hybrid system that comprises two microwave cavities, two nitrogen-vacancy center ensembles (NV ensembles), two optical cavities, and an optical fiber. Each NV ensemble serves as a quantum transducer, dispersively coupling with a microwave cavity and an optical cavity, which enables the conversion of quantum states between a microwave cavity and an optical cavity. The optical fiber acts as a connector between the two optical cavities. Numerical simulations demonstrate that our method allows for the transfer of an arbitrary photonic qubit state between two spatially separated microwave cavities with high fidelity. Furthermore, the method exhibits robustness against environmental decay, parameter fluctuations, and additive white Gaussian noise. Our approach offers a promising way for achieving long-distance transmission of quantum states between two spatially separated microwave cavities, which may have practical applications in networked large-scale quantum information processing and quantum communication.

Genome-wide identification of the alkaloid synthesis gene family CYP450, gives new insights into alkaloid resource utilization in medicinal Dendrobium.

The medicinal Dendrobium species of Orchidaceae possess significant pharmaceutical value, and modern pharmacological research has shown that Dendrobium contains many important active ingredients. Alkaloids, the crucial components of medicinal Dendrobium, demonstrate beneficial healing properties in cardiovascular, cataract, gastrointestinal, and respiratory diseases. Members of the cytochrome P450 monooxygenase (CYP) gene family play essential roles in alkaloid synthesis, participating in alkaloid terpene skeleton construction and subsequent modifications. Although studies of the CYP family have been conducted in some species, genome-wide characterization and systematic analysis of the CYP family in medicinal Dendrobium remain underexplored. In this study, we identified CYP gene family members in the genomes of four medicinal Dendrobium species recorded in the Pharmacopoeia: D. nobile, D. chrysotoxum, D. catenatum, and D. huoshanense. Further, we analyzed the motif composition, gene replication events, and selection pressure of this family. Syntenic analysis revealed that members of the clan 710 were present on chromosome 18 in three medicinal Dendrobium species, except for D. nobile, indicating a loss of clan 710 occurring in D. nobile. We also conducted an initial screening of the CYP genes involved in alkaloid synthesis through transcriptome sequencing. Quantitative real-time reverse transcription PCR showed that the expression of DnoNew43 and DnoNew50, homologs of secologanin synthase involved in the alkaloid synthesis pathway, was significantly higher in the stems than in the leaves. This result coincided with the distribution of dendrobine content in Dendrobium stems and leaves, indicating that these two genes might be involved in the dendrobine synthesis pathway. Our results give insights into the CYP gene family evolution analysis in four medicinal Dendrobium species for the first time and identify two related genes that may be involved in alkaloid synthesis, providing a valuable resource for further investigations into alkaloid synthesis pathway in Dendrobium and other medicinal plants.

Selection and validation of optimal reference genes for RT-qPCR analyses in Aphidoletes aphidimyza Rondani (Diptera: Cecidomyiidae).

Aphidoletes aphidimyza is a predator that is an important biological agent used to control agricultural and forestry aphids. Although many studies have investigated its biological and ecological characteristics, few molecular studies have been reported. The current study was performed to identify suitable reference genes to facilitate future gene expression and function analyses via quantitative reverse transcription PCR. Eight reference genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH), RPS13, RPL8, RPS3, α-Tub, ß-actin, RPL32, and elongation factor 1 alpha (EF1-α) were selected. Their expression levels were determined under four different experimental conditions (developmental stages, adult tissues, sugar treatment, and starvation treatment) using qRT-PCR technology. The stability was evaluated with five methods (Ct value, geNorm, NormFinder, BestKeeper, and RefFinder). The results showed that GAPDH, RPL32, and EF1-α were ranked as the best reference gene combinations for measuring gene expression levels among different developing stages and in various starvation treatments. RPL8 and RPS3 were recommended to normalize the gene expression levels among different adult tissues. RPL32, ß-actin, and EF1-α were recommended sugar-feeding conditions. To validate the utility of the selected reference pair, RPL8, and RPS3, we estimated the tissue-biased expression level of a chemosensory protein gene (AaphCSP1). As expected, AaphCSP1 is highly expressed in the antennae and lowly expressed in the abdomen. These findings will lay the foundation for future research on the molecular physiology and biochemistry of A. aphidimyza.

Revisiting the type species of the genus Homidia (Collembola, Entomobryidae).

Homidiacingula Börner, 1906, the type species of the genus Homidia Börner, 1906, is widespread from India to Southeast Asia, but its detailed morphological characteristics have not yet been described. We examined the morphology of specimens of H.cingula from Indonesia and southwestern China and confirmed their conspecific status by comparing their DNA barcoding sequences. We also compared the morphology of H.cingula with other two closely related species, confirming the valid species status of H.subcingula Denis, 1948. Our study provides new taxonomic and molecular data for the genus Homidia.

Nanotechnology boosts the efficiency of tumor diagnosis and therapy.

The incidence and mortality of cancer are gradually increasing. The highly invasive and metastasis of tumor cells increase the difficulty of diagnosis and treatment, so people pay more and more attention to the diagnosis and treatment of cancer. Conventional treatment methods, including surgery, radiotherapy and chemotherapy, are difficult to eliminate tumor cells completely. And the emergence of nanotechnology has boosted the efficiency of tumor diagnosis and therapy. Herein, the research progress of nanotechnology used for tumor diagnosis and treatment is reviewed, and the emerging detection technology and the application of nanodrugs in clinic are summarized and prospected. The first part refers to the application of different nanomaterials for imaging in vivo and detection in vitro, which includes magnetic resonance imaging, fluorescence imaging, photoacoustic imaging and biomarker detection. The distinctive physical and chemical advantages of nanomaterials can improve the detection sensitivity and accuracy to achieve tumor detection in early stage. The second part is about the nanodrug used in clinic for tumor treatment. Nanomaterials have been widely used as drug carriers, including the albumin paclitaxel, liposome drugs, mRNA-LNP, protein nanocages, micelles, membrane nanocomplexes, microspheres et al., which could improve the drug accumulate in tumor tissue through enhanced permeability and retention effect to kill tumor cells with high efficiency. But there are still some challenges to revolutionize traditional tumor diagnosis and anti-drug resistance based on nanotechnology.

An ontology-based approach for harmonization and cross-cohort query of Alzheimer's disease data resources.

BACKGROUND: In the United States, the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) are two major data sharing resources for Alzheimer's Disease (AD) research. NACC and ADNI strive to make their data more FAIR (findable, interoperable, accessible and reusable) for the broader research community. However, there is limited work harmonizing and supporting cross-cohort interoperability of the two resources. METHOD: In this paper, we leverage an ontology-based approach to harmonize data elements in the two resources and develop a web-based query system to search patient cohorts across the two resources. We first mapped data elements across NACC and ADNI, and performed value harmonization for the mapped data elements with inconsistent permissible values. Then we built an Alzheimer's Disease Data Element Ontology (ADEO) to model the mapped data elements in NACC and ADNI. We further developed a prototype cross-cohort query system to search patient cohorts across NACC and ADNI. RESULTS: After manual review, we found 172 mappings between NACC and ADNI. These 172 mappings were further used to construct common concepts in ADEO. Our data element mapping and harmonization resulted in five files storing common concepts, variables in NACC and ADNI, mappings between variables and common concepts, permissible values of categorical type data elements, and coding inconsistency harmonization, respectively. Our cross-cohort query system consists of three core architectural elements: a web-based interface, an advanced query engine, and a backend MongoDB database. CONCLUSIONS: In this work, ADEO has been specifically designed to facilitate data harmonization and cross-cohort query of NACC and ADNI data resources. Although our prototype cross-cohort query system was developed for exploring NACC and ADNI, its backend and frontend framework has been designed and implemented to be generally applicable to other domains for querying patient cohorts from multiple heterogeneous data sources.

Recent COVID-19 infection is associated with increased mortality in the ambulatory surgery population.

BACKGROUND: The effect of COVID-19 infection on post-operative mortality and the optimal timing to perform ambulatory surgery from diagnosis date remains unclear in this population. Our study was to determine whether a history of COVID-19 diagnosis leads to a higher risk of all-cause mortality following ambulatory surgery. METHODS: This cohort constitutes retrospective data obtained from the Optum dataset containing 44,976 US adults who were tested for COVID-19 up to 6 months before surgery and underwent ambulatory surgery between March 2020 to March 2021. The primary outcome was the risk of all-cause mortality between the COVID-19 positive and negative patients grouped according to the time interval from COVID-19 testing to ambulatory surgery, called the Testing to Surgery Interval Mortality (TSIM) of up to 6 months. Secondary outcome included determining all-cause mortality (TSIM) in time intervals of 0-15 days, 16-30 days, 31-45 days, and 46-180 days in COVID-19 positive and negative patients. RESULTS: 44,934 patients (4297 COVID-19 positive, 40,637 COVID-19 negative) were included in our analysis. COVID-19 positive patients undergoing ambulatory surgery had higher risk of all-cause mortality compared to COVID-19 negative patients (OR = 2.51, p < 0.001). The increased risk of mortality in COVID-19 positive patients remained high amongst patients who had surgery 0-45 days from date of COVID-19 testing. In addition, COVID-19 positive patients who underwent colonoscopy (OR = 0.21, p = 0.01) and plastic and orthopedic surgery (OR = 0.27, p = 0.01) had lower mortality than those underwent other surgeries. CONCLUSIONS: A COVID-19 positive diagnosis is associated with significantly higher risk of all-cause mortality following ambulatory surgery. This mortality risk is greatest in patients that undergo ambulatory surgery within 45 days of testing positive for COVID-19. Postponing elective ambulatory surgeries in patients that test positive for COVID-19 infection within 45 days of surgery date should be considered, although prospective studies are needed to assess this.

Transiently impaired endothelial function during thyroid hormone withdrawal in differentiated thyroid cancer patients.

Purpose: Endothelial dysfunction, which was associated with chronic hypothyroidism, was an early event in atherosclerosis. Whether short-term hypothyroidism following thyroxine withdrawal during radioiodine (RAI) therapy was associated with endothelial dysfunction in patients with differentiated thyroid cancer (DTC) was unclear. Aim of the study was to assess whether short-term hypothyroidism could impair endothelial function and the accompanied metabolic changes in the whole process of RAI therapy. Methods: We recruited fifty-one patients who underwent total thyroidectomy surgery and would accept RAI therapy for DTC. We analyzed thyroid function, endothelial function and serum lipids levels of the patients at three time points: the day before thyroxine withdrawal(P1), the day before 131I administration(P2) and 4-6 weeks after RAI therapy(P3). A high-resolution ultrasound named flow-mediated dilation (FMD) was used to measure endothelial function of the patients. Results: We analyzed the changes of FMD, thyroid function and lipids at three time points. FMD(P2) decreased significantly compared to FMD(P1) (P1vsP2, 8.05 ± 1.55vs 7.26 ± 1.50, p<0.001). There was no significant difference between FMD(P3) and FMD(P1) after restoring TSH (thyroid stimulating hormone) suppression therapy (P1 vs P3, 8.05 ± 1.55 vs 7.79 ± 1.38, p=0.146). Among all parameters, the change of low-density lipoprotein (ΔLDL) was the only factor correlated negatively with the change of FMD (ΔFMD) throughout the RAI therapy process (P1-2, r=-0.326, p=0.020; P2-3, r=-0.306, p=0.029). Conclusion: Endothelial function was transiently impaired in DTC patients at short-term hypothyroidism state during the RAI therapy, and immediately returned to the initial state after restoring TSH suppression therapy.

Interleukin-6 promotes the dedifferentiation of papillary thyroid cancer cells.

Radioiodine treatment is a fundamental therapy for patients with papillary thyroid cancer (PTC). Sodium/iodide symporter (NIS)-mediated iodine uptake is a prerequisite for the efficacy of radioiodine therapy. Interleukin-6 (IL-6) is a pro-tumor cytokine, but its regulation of NIS expression in PTC has not been elucidated. In this study, we found that IL-6 enhanced the proliferation ability of PTC cells. Moreover, the negative association between IL-6 and NIS expression in thyroid cancer tissues was demonstrated. IL-6 downregulated thyroid-specific genes such as NIS, thyroid peroxidase, and thyroid-stimulating hormone receptor and thyroid-specific transcription factors including thyroid transcription factor-1 (TTF-1) and paired box protein-8 (PAX-8). The inhibitory effects of IL-6 on NIS expression were alleviated by mitogen-activated protein kinase and Janus kinase inhibitors. Depletion of c-Jun or STAT3 also rescued IL-6-induced NIS downregulation, with STAT3 depletion exerting a stronger effect. TTF-1 protein expression was also restored by depleting c-Jun or STAT3. STAT3 depletion, but not c-Jun depletion, alleviated the inhibitory effect of IL-6 on PAX-8 expression. Moreover, the downregulation of NIS by IL-6 was rescued by overexpressing TTF-1 and PAX-8. Tocilizumab, an IL-6 receptor blocker, did not have any cytostatic activity in PTC cells, and it also failed to induce redifferentiation in vitro. However, we found that the drug blocked the inhibitory effect of IL-6 on NIS expression. In summary, IL-6 inhibits NIS transcription in PTC cells by activating mitogen-activated protein kinase and Janus kinase signaling.

A UMLS-based Investigation of Laterality in Biomedical Terminologies.

Laterality is an important anatomic directional property indicating the sidedness of body structures, diseases, and procedures. Errors in laterality could have catastrophic consequences in patient care. In this paper, we investigate how different biomedical terminologies organize terms indicating laterality. We leverage the Unified Medical Language System (UMLS) to identify lateral terms in different terminologies. For each lateral term, we attempt to obtain other matched lateral terms and further analyze how they are interrelated. Our results indicated that only 1.68% of the matched lateral term-pairs are hierarchically related. It was also seen that 44.24% of matched-pairs were siblings. We found that in SNOMED CT, bilateral concepts were hierarchically related to both left and right lateral concepts different to most other terminologies. Further investigation revealed that the likely causes for these relations are how the logical definitions of SNOMED CT concepts are arranged.

Data Mining Pipeline for COVID-19 Vaccine Safety Analysis Using a Large Electronic Health Record.

We developed a novel data mining pipeline that automatically extracts potential COVID-19 vaccine-related adverse events from a large Electronic Health Record (EHR) dataset. We applied this pipeline to Optum® de-identified COVID-19 EHR dataset containing COVID-19 vaccine records between December 11, 2020 and January 20, 2022. We compared post-vaccination diagnoses between the COVID-19 vaccine group and the influenza vaccine group among 553,682 individuals without COVID-19 infection. We extracted 1,414 ICD-10 diagnosis categories (first three ICD10 digits) within 180 days after the first dose of the COVID-19 vaccine. We then ranked the diagnosis codes using the adverse event rates and adjusted odds ratio based on the self-controlled case series analysis. Using inverse probability of censoring weighting, we estimated the right-censored time-to-event records. Our results show that the COVID-19 vaccine has a similar adverse events rate to the influenza vaccine. We found 20 types of potential COVID-19 vaccine-related adverse events that may need further investigation.

A Query Engine for Self-controlled Case Series, with an application to COVID-19 EHR data.

Self-controlled case series (SCCS) is a statistical method in epidemiological study design that uses individuals as their own controls, with comparisons made within the same individuals at different time points of observation. SCCS has been applied in settings where it is difficult to identify comparison or control groups. To provide computational support for SCCS, we introduce a query engine called Self-Controlled Case Query (SCCQ) and use it to extract cohorts of self-controlled case series from a large-scale COVID-19 Electronic Health Records (EHR) dataset. Visual summary of the queried population through the R-Shiny visualization framework offers SCCQ's query result dashboard to the researcher. SCCQ allows the export of query-generated raw data files with a portable format that researchers can extend to create more intricate and robust visualization capabilities without needing a high-level of technical or statistical background. Our validation and evaluation experiments uncovered COVID-19 outcomes to be consistent with existing research findings. With SCCQ, cohort exploration, data extraction, and information visualization can be provided for structured EHR data to lower the barrier for clinical and epidemiological research.

Extracting Temporal Expressions of First Seizure Onset from Epilepsy Patient Discharge Summaries.

Early onset of seizure is a potential risk factor for Sudden Unexpected Death in Epilepsy (SUDEP). However, the first seizure onset information is often documented as clinical narratives in epilepsy monitoring unit (EMU) discharge summaries. Manually extracting first seizure onset time from discharge summaries is time consuming and labor-intensive. In this work, we developed a rule-based natural language processing pipeline for automatically extracting the temporal information of patients' first seizure onset from EMU discharge summaries. We use the Epilepsy and Seizure Ontology (EpSO) as the core knowledge resource and construct 4 extraction rules based on 300 randomly selected EMU discharge summaries. To evaluate the effectiveness of the extraction pipeline, we apply the constructed rules on another 200 unseen discharge summaries and compare the results against the manual evaluation of a domain expert. Overall, our extraction pipeline achieved a precision of 0.75, recall of 0.651, and F1-score of 0.697. This is an encouraging initial result which will allow us to gain insights into potentially better-performing approaches.

Successful treatment of lichen amyloidosis coexisting with atopic dermatitis by dupilumab: Four case reports.

BACKGROUND: Lichen amyloidosis (LA) is a chronic, severely pruritic skin disease, which is the most common form of primary cutaneous amyloidosis. The treatment of LA has been considered to be difficult. LA may be associated with atopic dermatitis (AD), and in this setting, the treatment options may be more limited. Herein, we report four cases of LA associated with AD successfully treated by dupilumab. CASE SUMMARY: In this article, we describe four cases of patients who presented with recurrent skin rash accompanied by severe generalized intractable pruritus, diagnosed with refractory LA coexisting with chronic AD. Previous treatments had not produced any apparent improvement. Thus, we administered dupilumab injection subcutaneously at a dose of 600 mg for the first time and 300 mg every 2 wk thereafter. Their lesions all markedly improved. CONCLUSION: Dupilumab may be a new useful treatment for LA coexisting with AD.

p53-Dependent ferroptosis pathways in sepsis.

Sepsis is caused by complex infections, trauma, and major surgery that results in high morbidity and mortality. As one of the leading causes of death in the intensive care unit (ICU）, sepsis causes organ dysfunction and death via a vicious cycle of uncontrolled inflammatory responses and immunosuppression. Ferroptosis is an iron-dependent cellular death pathway driven by the accumulation of lipid peroxides, which occurs in sepsis. p53 is an important regulator of ferroptosis. Under intracellular/extracellular stimulation and pressure, p53 acts as a transcription factor to regulate the expression of downstream genes, which help cells/bodies to resist stimuli. p53 can also function independently as an important mediator. The understanding of key cellular and molecular mechanisms of ferroptosis facilitates the prognosis of sepsis. This article describes the molecular mechanism and role of p53 in sepsis-induced ferroptosis, and introduces some potential therapeutic targets for sepsis-induced ferroptosis, which highlights the dominant and potential therapeutic role of p53 in sepsis. Keywords: p53, acetylation, Sirt3, ferroptosis, sepsis, therapy.

Dl-3-n-butylphthalide improves intestinal microcirculation disorders in septic rats by regulating the PI3K/AKT signaling pathway and autophagy.

PURPOSE: Sepsis has complex pathophysiological mechanisms that bring new challenges in the treatment of sepsis at a time when the intestinal microcirculation in sepsis is receiving increasing attention. Dl-3-n-butylphthalide (NBP), which is a drug that can improve multiorgan ischemic diseases, is also worth examining to improve the intestinal microcirculation in sepsis. METHODS: In this study, male Sprague-Dawley rats were divided into the sham group (n = 6), CLP group (n = 6), NBP group (n = 6) and NBP + LY294002 group (n = 6). The rat model of severe sepsis was established by cecal ligation and puncture (CLP). Abdominal wall incisions and sutures were performed in the first group, and CLP was performed in the latter three groups. Normal saline/NBP/NBP + LY294002 solution was injected intraperitoneally 2 h or 1 h before modeling. Hemodynamic data (blood pressure and heart rate) were recorded at 0, 2, 4 and 6 h. Sidestream dark field (SDF) imaging and the Medsoft System were used to observe the intestinal microcirculation of rats and obtain data at 0, 2, 4, and 6 h. Six hours after the model was established, the serum levels of TNF-α and IL-6 were measured to evaluate the level of systemic inflammation. Pathological damage to the small intestine was evaluated by electron microscopy and histological analysis. The expression levels of P-PI3K, PI3K, P-AKT, AKT, LC3 and p62 in the small intestine were analyzed by Western blotting. The expressions of P-PI3K, P-AKT, LC3 and P62 in small intestine were detected by immunohistochemical staining. RESULTS: NBP improved intestinal microcirculation disturbances in septic rats, alleviated the systemic inflammatory response, reduced the destruction of the small intestinal mucosa and the disruption of microvascular endothelial cells, and alleviated autophagy in vascular endothelial cells. NBP increased the ratio of P-PI3K/total PI3K, P-AKT/total AKT, and P62/ß-actin and decreased the ratio of LC3 II/LC3 I. CONCLUSION: NBP ameliorated intestinal microcirculation disturbances and the destruction of small intestinal vascular endothelial cells in septic rats by activating the PI3K/Akt signaling pathway and regulating autophagy.