Analysis of gut microbiota-derived metabolites regulating pituitary neuroendocrine tumors through network pharmacology.

Pituitary neuroendocrine tumors (PitNETs) are a special class of tumors of the central nervous system that are closely related to metabolism, endocrine functions, and immunity. In this study, network pharmacology was used to explore the metabolites and pharmacological mechanisms of PitNET regulation by gut microbiota. The metabolites of the gut microbiota were obtained from the gutMGene database, and the targets related to the metabolites and PitNETs were determined using public databases. A total of 208 metabolites were mined from the gutMGene database; 1,192 metabolite targets were screened from the similarity ensemble approach database; and 2,303 PitNET-related targets were screened from the GeneCards database. From these, 392 overlapping targets were screened between the metabolite and PitNET-related targets, and the intersection between these overlapping and gutMGene database targets (223 targets) were obtained as the core targets (43 targets). Using the protein-protein interaction (PPI) network analysis, Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway and metabolic pathway analysis, CXCL8 was obtained as a hub target, tryptophan metabolism was found to be a key metabolic pathway, and IL-17 signaling was screened as the key KEGG signaling pathway. In addition, molecular docking analysis of the active metabolites and target were performed, and the results showed that baicalin, baicalein, and compound K had good binding activities with CXCL8. We also describe the potential mechanisms for treating PitNETs using the information on the microbiota (Bifidobacterium adolescentis), signaling pathway (IL-17), target (CXCL8), and metabolites (baicalin, baicalein, and compound K); we expect that these will provide a scientific basis for further study.

A nomogram to predict 28-day mortality in patients with sepsis combined coronary artery disease: retrospective study based on the MIMIC-III database.

Object: Establish a clinical prognosis model of coronary heart disease (CHD) to predict 28-day mortality in patients with sepsis. Method: The data were collected retrospectively from septic patients with a previous history of coronary heart disease (CHD) from the Medical Information Mart for Intensive Care (MIMIC)-III database. The included patients were randomly divided into the training cohorts and validation cohorts. The variables were selected using the backward stepwise selection method of Cox regression, and a nomogram was subsequently constructed. The nomogram was compared to the Sequential Organ Failure Assessment (SOFA) model using the C-index, area under the receiver operating characteristic curve (AUC) over time, Net reclassification index (NRI), Integrated discrimination improvement index (IDI), calibration map, and decision curve analysis (DCA). Result: A total of 800 patients were included in the study. We developed a nomogram based on age, diastolic blood pressure (DBP), pH, lactate, red blood cell distribution width (RDW), anion gap, valvular heart disease, peripheral vascular disease, and acute kidney injury (AKI) stage. The nomogram was evaluated using C-index, AUC, NRI, IDI, calibration plot, and DCA. Our findings revealed that this nomogram outperformed the SOFA score in predicting 28-day mortality in sepsis patients.

The correlation between patients with type 2 diabetes mellitus and chronic microvascular complications during the glucose peak time.

INTRODUCTION: To assess the Type 2 Diabetes Mellitus (T2DM) patients in association with Chronic Microvascular Complications at Glucose Peak Time and the association among chronic microvascular complications in T2DM patients and the glucose peak period in the typical steamed bread meal test. METHODS: Overall 1095 T2DM patients were classified as three groups: (1) Group G1: glucose peak time ≤ 1 h (n = 84), Group G2: 1 h < glucose peak time ≤ 2 h (n = 648) and Group G3: glucose peak time > 2 h (n = 363). The clinical characteristics, insulin characteristics and glucose peak time and chronic microvascular complications markers of patients in each group was analyzed and compared. Statistical analyses were performed using SPSS 23.0, employing chi-square tests, Kruskal-Wallis tests, one-way ANOVA, and binary logistic regression analysis, with significance set at P < 0.05. RESULTS: Age, length of disease, glycated hemoglobin (HbA1c), urine albumin-creatinine ratio (UACR), and the number of patients with diabetic retinopathy (DR) increased (all P < 0.05) in those with postponed glucose peak time, while insulinogenic indexes, the AUC for C-p (AUCC-p), fasting, and 120-min C-peptide (C-p) decreased (all P < 0.05). Only age was connected to patients with diabetic kidney disease (DKD) independently in binary logistic regression analysis, although delayed glucose peak time was related to the presence of patients with DR. (all P < 0.05). CONCLUSION: Delayed glucose peak time contributed to DR. Attention should be paid to condition of chronic microvascular complications in T2DM patients with a postponed peak glucose timing.

Bacteroides uniformis degrades ß-glucan to promote Lactobacillus johnsonii improving indole-3-lactic acid levels in alleviating colitis.

BACKGROUND: Intake of dietary fiber is associated with a reduced risk of inflammatory bowel disease. ß-Glucan (BG), a bioactive dietary fiber, has potential health-promoting effects on intestinal functions; however, the underlying mechanism remains unclear. Here, we explore the role of BG in ameliorating colitis by modulating key bacteria and metabolites, confirmed by multiple validation experiments and loss-of-function studies, and reveal a novel bacterial cross-feeding interaction. RESULTS: BG intervention ameliorates colitis and reverses Lactobacillus reduction in colitic mice, and Lactobacillus abundance was significantly negatively correlated with the severity of colitis. It was confirmed by further studies that Lactobacillus johnsonii was the most significantly enriched Lactobacillus spp. Multi-omics analysis revealed that L. johnsonii produced abundant indole-3-lactic acid (ILA) leading to the activation of aryl hydrocarbon receptor (AhR) responsible for the mitigation of colitis. Interestingly, L. johnsonii cannot utilize BG but requires a cross-feeding with Bacteroides uniformis, which degrades BG and produces nicotinamide (NAM) to promote the growth of L. johnsonii. A proof-of-concept study confirmed that BG increases L. johnsonii and B. uniformis abundance and ILA levels in healthy individuals. CONCLUSIONS: These findings demonstrate the mechanism by which BG ameliorates colitis via L. johnsonii-ILA-AhR axis and reveal the important cross-feeding interaction between L. johnsonii and B. uniformis. Video Abstract.

Underlying mechanisms and management strategies for regorafenib-induced toxicity in hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) accounts for 85% of liver cancer cases and is the third leading cause of cancer death. Regorafenib is a multi-target inhibitor that dramatically prolongs progression-free survival in HCC patients who have failed sorafenib therapy. However, one of the primary factors limiting regorafenib's clinical utilization is toxicity. Using Clinical Trials.gov and PubMed, we gathered clinical data on regorafenib and conducted a extensive analysis of the medication's adverse reactions and mechanisms. Next, we suggested suitable management techniques to improve regorafenib's effectiveness. AREAS COVERED: We have reviewed the mechanisms by which regorafenib-induced toxicity occurs and general management strategies through clinical trials of regorafenib. Furthermore, by examining the literature on regorafenib and other tyrosine kinase inhibition, we summarized the mechanics of the onset of regorafenib toxicity and mechanism-based intervention strategies by reviewing the literature related to regorafenib and other tyrosine kinase inhibition. EXPERT OPINION: One of the primary factors restricting regorafenib's clinical utilization and combination therapy is its toxicity reactions. To optimize regorafenib treatment regimens, it is especially important to further understand the specific toxicity mechanisms of regorafenib as a multi-kinase inhibitor.

On-site SERS analysis and intelligent multi-identification of fentanyl class substances by deep machine learning.

As the types of fentanyl class substances continue to grow, a universal SERS sensor is essential for the application of discriminant detection of fentanyl substances. A new nanomaterial SERS sensor-Ag@Au NPs-paper was developed. The SERS sensitivity and stability of Ag@Au NPs-paper were investigated by using R6G molecule, and the results showed that Ag@Au NPs-paper has excellent performance. In combination with visual analysis and machine learning methods, Ag@Au NPs-paper has been successfully applied to the analysis of fentanyl class substances and the component identification of binary fentanyl mixtures, and thus it can be effectively used in food safety, environmental toxicants and other fields.

The activation of the HIF-1α-VEGFA-Notch1 signaling pathway by Hydroxysafflor yellow A promotes angiogenesis and reduces myocardial ischemia-reperfusion injury.

Hydroxyl Safflower Yellow A (HSYA) is the primary bioactive compound derived from Safflower, which has been scientifically proven to possess anti-inflammatory, anti-apoptotic, and ameliorative properties against mitochondrial damage during acute myocardial ischemia-reperfusion injury (MIRI); however, its effects during the recovery stage remain unknown. Angiogenesis plays a crucial role in the rehabilitation process. AIM OF THE STUDY: The objective of this study was to investigate the long-term angiogenic effect of HSYA and its contribution to recovery after myocardial ischemia, as well as explore its underlying mechanism using non-targeted metabolomics and network pharmacology. MATERIALS AND METHODS: The MIRI model in rat was established by ligating the left anterior descending branch of the coronary artery. The effect of HSYA was assessed based on myocardial infarction volume and histopathology. Immunofluorescence staining was employed to evaluate angiogenesis, while ELISA was used to detect markers of myocardial injury. Additionally, a rat myocardial microvascular endothelial cell (CMECs) injury model was established using oxygen-glucose deprivation/reoxygenation (OGD/R), followed by scratch assays, migration assays, and tube formation experiments to assess angiogenesis. Western blot analysis was conducted to validate the underlying mechanism. RESULTS: Our findings provide compelling evidence for the therapeutic efficacy of HSYA in reducing myocardial infarction size, facilitating cardiac functional recovery, and reversing pathological alterations within the heart. Furthermore, we elucidate that HSYA exerts its effects on promoting migration and generation of myocardial microvascular endothelial cells through activation of the HIF-1α-VEGFA-Notch1 signaling pathway. CONCLUSION: These results underscore how HSYA enhances cardiac function via angiogenesis promotion and activation of the aforementioned signaling cascade.

Maintenance of magnesium homeostasis by NUF2 promotes protein synthesis and anaplastic thyroid cancer progression.

Thyroid cancer is the most frequently observed endocrine-related malignancy among which anaplastic thyroid cancer (ATC) is the most fatal subtype. The synthesis of protein is active to satisfy the rapid growth of ATC tumor, but the mechanisms regulating protein synthesis are still unknown. Our research revealed that kinetochore protein NUF2 played an essential role in protein synthesis and drove the progression of ATC. The prognosis of patients with thyroid carcinoma was positively correlated with high NUF2 expression. Depletion of NUF2 in ATC cells notably inhibited the proliferation and induced apoptosis, while overexpression of NUF2 facilitated ATC cell viability and colony formation. Deletion of NUF2 significantly suppressed the growth and metastasis of ATC in vivo. Notably, knockdown of NUF2 epigenetically inhibited the expression of magnesium transporters through reducing the abundance of H3K4me3 at promoters, thereby reduced intracellular Mg2+ concentration. Furthermore, we found the deletion of NUF2 or magnesium transporters significantly inhibited the protein synthesis mediated by the PI3K/Akt/mTOR pathway. In conclusion, NUF2 functions as an emerging regulator for protein synthesis by maintaining the homeostasis of intracellular Mg2+, which finally drives ATC progression.

Drug-Induced Gynecomastia: Data Mining and Analysis of the FDA Adverse Event Reporting System Database.

Purpose: Drug-induced gynecomastia significantly affects patient health and quality of life. This study aimed to perform an exploratory analysis of gynecomastia reports and the most commonly associated medications within the FAERS database. Patients and Methods: A comprehensive analysis of the FAERS from January 2004 to December 2023 was conducted. Disproportionality analysis and subsequent sensitivity analysis were performed to identify drugs potentially associated with gynecomastia, utilizing the reported odds ratio (ROR). Logistic regression analysis was employed to assess potential risk factors. The Weibull shape parameter (WSP) test was used to assess the time-to-onset characteristics of the top drugs associated with gynecomastia. Results: The study identified 30,265 cases of gynecomastia, primarily associated with nervous system drugs, accounting for 85.50% of cases. Notably, risperidone accounted for 80.81% of the total cases. Among the 165 agents with ≥ 5 cases of gynecomastia, the strongest signals were exhibited by risperidone (ROR 602.38, 95% CI 585.07-620.20), dutasteride (ROR 17.18, 95% CI 15.55-18.89), spironolactone (ROR 15.8, 95% CI 13.99-17.83), and paliperidone (ROR 7.16, 95% CI 6.55-7.84). In the sensitivity analysis of disproportionality, unexpected associations were observed, such as montelukast (n = 21, ROR 1.94, 95% CI 1.26-2.98). The logistic regression analysis indicated that the risk of risperidone-induced gynecomastia was significantly lower in adults compared to pediatric patients (OR 0.12, 95% CI 0.09-0.15) and in patients with higher body weight than in those with lower body weight (OR 5.24, 95% CI 3.62-7.76). The WSP test showed that gynecomastia induced by most of the top 10 common agents tends to occur in an early failure mode. Conclusion: The rankings and signal strengths of drugs associated with gynecomastia were extracted from the FAERS. The age distribution and time-to-onset distribution of the top 10 drugs linked to gynecomastia were investigated, which can facilitate accurate clinical recognition of drug-induced gynecomastia.

The evolutionary features and roles of single nucleotide variants and charged amino acid mutations in influenza outbreaks during NPI period.

The epidemic and outbreaks of influenza B Victoria lineage (Bv) during 2019-2022 led to an analysis of genetic, epitopes, charged amino acids and Bv outbreaks. Based on the National Influenza Surveillance Network (NISN), the Bv 72 strains isolated during 2019-2022 were selected by spatio-temporal sampling, then were sequenced. Using the Compare Means, Correlate and Cluster, the outbreak data were analyzed, including the single nucleotide variant (SNV), amino acid (AA), epitope, evolutionary rate (ER), Shannon entropy value (SV), charged amino acid and outbreak. With the emergence of COVID-19, the non-pharmaceutical interventions (NPIs) made Less distant transmission and only Bv outbreak. The 2021-2022 strains in the HA genes were located in the same subset, but were distinct from the 2019-2020 strains (P < 0.001). The codon G → A transition in nucleotide was in the highest ratio but the transversion of C → A and T → A made the most significant contribution to the outbreaks, while the increase in amino acid mutations characterized by polar, acidic and basic signatures played a key role in the Bv epidemic in 2021-2022. Both ER and SV were positively correlated in HA genes (R = 0.690) and NA genes (R = 0.711), respectively, however, the number of mutations in the HA genes was 1.59 times higher than that of the NA gene (2.15/1.36) from the beginning of 2020 to 2022. The positively selective sites 174, 199, 214 and 563 in HA genes and the sites 73 and 384 in NA genes were evolutionarily selected in the 2021-2022 influenza outbreaks. Overall, the prevalent factors related to 2021-2022 influenza outbreaks included epidemic timing, Tv, Ts, Tv/Ts, P137 (B → P), P148 (B → P), P199 (P → A), P212 (P → A), P214 (H → P) and P563 (B → P). The preference of amino acid mutations for charge/pH could influence the epidemic/outbreak trends of infectious diseases. Here was a good model of the evolution of infectious disease pathogens. This study, on account of further exploration of virology, genetics, bioinformatics and outbreak information, might facilitate further understanding of their deep interaction mechanisms in the spread of infectious diseases.

Investigating the Effect of High-Voltage Electrostatic Field (HVEF) Treatment on the Physicochemical Characteristics, Bioactive Substances Content, and Shelf Life of Tomatoes.

This study evaluated the ability of a high-voltage electrostatic field (HVEF) treatment to extend the shelf life of tomatoes. Tomatoes were exposed to HVEF treatment for different lengths of time, and the physicochemical properties of tomatoes and bioactive compounds were monitored during 28 days of storage at 4 °C. The results indicated that the quality parameters of tomatoes were better maintained during storage by the HVEF treatment relative to the control treatment, extending their shelf life by 14-28 days. The HVEF treatment mitigated losses in firmness, weight, color changes, and bioactive substances, such as total phenolic content, total flavonoid content, ascorbic acid, and lycopene. The activity of pectin-degrading enzymes was also inhibited. The best exposure times for the HVEF treatment were 90 and 120 min. While the measured parameters decreased in both the control and HVEF treatment groups, the decrease in all of these measured parameters was significantly less (p < 0.05) in the optimum HVEF treatment groups than in the control. While the physicochemical properties may vary between different tomato varieties, the HVEF treatment of harvested tomatoes for 90 or 120 min can mitigate the degradation of quality parameters and loss of bioactive compounds incurred during the postharvest storage of tomatoes, thus maintaining their commercial value.

18ß-Glycyrrhetinic acid synergizes with enzalutamide to counteract castration-resistant prostate cancer by inhibiting OATP2B1 uptake of dehydroepiandrosterone sulfate.

Androgen dependence is a key feature of prostate cancer, and androgen deprivation is effective in treating prostate cancer. However, the disease often worsens and develops into castration-resistant prostate cancer after short-term control. The current study aimed to explore the mechanism of the synergistic action of 18ß-glycyrrhetinic acid (18ß-GA) and enzalutamide (ENZ) against prostate cancer. Our findings showed that 18ß-GA significantly inhibited the expression of OATP2B1 and the transport of dehydroepiandrosterone sulfate (DHEAS) in LNCap and 22RV1 cells. It also downregulated the expression of androgen receptor (AR) to some extent. ENZ strongly inhibited AR expression, but it did not affect OATP2B1-mediated uptake of DHEAS. Compared to the effects of 18ß-GA and ENZ alone, the combination of 18ß-GA and ENZ significantly enhanced the inhibitory effects on AR, prostate-specific antigen (PSA) expression, tumor cell proliferation, and migration. The results obtained in castrated model mice matched the findings of in vitro experiments. 18ß-GA significantly reduced the uptake of DHEAS mediated by OATP2B1 in mouse tumor tissues and cooperated with ENZ to further inhibit the expression of AR and PSA, combat the growth of tumor cells, and promote the apoptosis of tumor cells. In conclusion, 18ß-GA considerably decreased the uptake of DHEAS and androgen production in cells by inhibiting the transport function of OATP2B1, while ENZ inhibited the nuclear translocation of AR and reduced the expression of AR. The combination of 18ß-GA and ENZ can simultaneously inhibit androgen production and AR expression and exhibit a synergistic effect against castration and prostate cancer progression.

Extensive Dysregulation of Phenylalanine Metabolism Is Associated With Stress Hyperphenylalaninemia and 30-Day Death in Critically Ill Patients With Acute Decompensated Heart Failure.

BACKGROUND: Stress hyperphenylalaninemia predicts elevated mortality rates in patients with acute decompensated heart failure (ADHF). This study investigated the metabolic pathways underlying this association and identified a unique metabolic phenotype underlying the association between stress hyperphenylalaninemia and adverse outcomes in ADHF. METHODS AND RESULTS: This was a retrospective cohort study. We enrolled 120 patients with ADHF in an intensive care unit (60 with a phenylalanine level ≥112 µM, 60 with a phenylalanine level <112 µM), and 30 controls. Plasma phenylalanine-derived metabolites were measured, and participants were evaluated for 30-day death. Patients with ADHF had extensive activations of the alternative pathways for metabolizing phenylalanine, leading to the levels of phenylalanine-derived downstream metabolites 1.5 to 6.1 times higher in patients with ADHF than in the controls (all P<0.001). Extensive dysregulation of these alternative pathways significantly increased phenylalanine levels and contributed to a distinct metabolic phenotype, characterized by increased phenylalanine, tyrosine, homogentisic acid, and succinylacetone levels but decreased benzoic acid and 3,4-dihydroxyphenylalanine levels. Throughout the 30-day follow-up period, 47 (39.2%) patients died. This distinct metabolic phenotype was associated with an increased mortality rate (odds ratio, 1.59 [95% CI, 1.27-1.99]; P<0.001). A multivariable analysis confirmed the independent association of this metabolic phenotype, in addition to phenylalanine and tyrosine levels, with 30-day death. CONCLUSIONS: In patients with ADHF, extensive dysregulation of the alternative pathways for metabolizing phenylalanine was correlated with stress hyperphenylalaninemia and a distinct metabolic phenotype on the phenylalanine-tyrosine-homogentisic acid-succinylacetone axis. Both stress hyperphenylalaninemia and metabolic dysregulation on this axis were associated with poor outcomes.

Schistosomicidal effects of histone acetyltransferase inhibitors against Schistosoma japonicum juveniles and adult worms in vitro.

BACKGROUND: Schistosomiasis is a relatively neglected parasitic disease that afflicts more than 250 million people worldwide, for which the control strategy relies mainly on mass treatment with the only available drug, praziquantel (PZQ). This approach is not sustainable and is a priority for developing novel drug candidates for the treatment and control of schistosomiasis. METHODOLOGYS/PRINCIPAL FINDINGS: In our previous study, we found that DW-3-15, a kind of PZQ derivative, could significantly downregulate the expression of the histone acetyltransferase of Schistosoma japonicum (SjHAT). In this study, several commercially available HAT inhibitors, A485, C646 and curcumin were screened in vitro to verify their antischistosomal activities against S. japonicum juveniles and adults. Parasitological studies and scanning electron microscopy were used to study the primary action characteristics of HAT inhibitors in vitro. Quantitative real-time PCR was employed to detect the mRNA level of SjHAT after treatment with different HAT inhibitors. Our results demonstrated that curcumin was the most effective inhibitor against both juveniles and adults of S. japonicum, and its schistosomicidal effects were time- and dose dependent. However, A485 and C646 had limited antischistosomal activity. Scanning electron microscopy demonstrated that in comparison with DW-3-15, curcumin caused similar tegumental changes in male adult worms. Furthermore, both curcumin and DW-3-15 significantly decreased the SjHAT mRNA level, and curcumin dose-dependently reduced the SjHAT expression level in female, male and juvenile worms. CONCLUSIONS: Among the three commercially available HATs, curcumin was the most potent against schistosomes. Both curcumin and our patent compound DW-3-15 markedly downregulated the expression of SjHAT, indicating that SjHAT may be a potential therapeutic target for developing novel antischistosomal drug candidates.

Insight into the autochthonous lactic acid bacteria as starter culture for improving the quality of Sichuan radish paocai: Changes in microbial diversity and metabolic profiles.

Paocai is a traditional Chinese fermented vegetable product popular in Asian countries. Recently, functional starters were used to control the fermentation process and improve the quality of paocai. In this study, three autochthonous lactic acid bacteria including Lactiplantibacillus plantarum LB6, Lactiplantibacillus pentosus LB3, and Weissella cibaria W51 were selected as starters and the effect of the starters on the fermentation of paocai was investigated. The results suggested that the inoculated fermentation led to a lower nitrite peak and more pronounced changes in pH and total titratable acid in the early stage of fermentation, compared with natural fermentation. Analysis of the flavor compounds indicated that the total content of volatile organic compounds of paocai through natural fermentation was significantly lower than that in inoculated fermentation. As for free amino acids, in the early stage of fermentation, the types and contents of free amino acids in the inoculated fermentation paocai were higher than those in the blank group. In the later stage of fermentation, the contents of amino acids representing umami and sweet tastes were also higher than those in the blank group. The bacterial community analysis showed that Lactobacillus and Lactococcus were the dominant bacteria in both inoculated fermentation and natural fermentation. Then, the correlations among physicochemical properties, microbial community and flavor compounds were revealed, and it was found that the dominant bacteria such as Lactococcus, Leuconostoc, Lactobacillus and Weissella displayed a considerable impact on the physical and chemical properties and flavor of paocai. In addition, the metabolic pathways involved in flavor formation and the abundance of related enzymes were elucidated. The abundance of enzymes involved in generating prephenic acid, 2-methylbutanoic acid, L-lactic acid, D-lactic acid, butanoic acid, etc., and in the pathway of producing flavor substances (His, Met, ethyl hexanoate, etc.) was up-regulated in the inoculated fermentation. Results presented in this study may provide a reference for the development of paocai starters and further guidance for the flavor improvement of Sichuan paocai.

Pulmonary adverse reaction caused by furazolidone: Two case reports and a literature review.

RATIONALE: As one of the drugs used to treat Helicobacter pylori, furazolidone has been reported to cause gastrointestinal reactions, allergies, dizziness, and more. However, its related drug-induced lung injury has been rarely reported. Furthermore, there have been no reports of the timing for initiating hormone therapy when a pulmonary adverse reaction occurs. PATIENT CONCERNS: We report 2 cases, both of them showed interlobular septal thickening and nodules on the chest computed tomography. One had more discomfort symptoms and had a higher eosinophil count than the normal range, while the other only had fever symptoms and had an eosinophil count within the normal range. DIAGNOSES: Pulmonary adverse reaction caused by furazolidone was diagnosed. INTERVENTIONS: Furazolidone was discontinued, and the person with increased eosinophils received hormone therapy, while the other person did not. OUTCOMES: After discontinuation of medication and treatment, the symptoms of the 2 patients gradually improved. LESSONS: This report suggests that furazolidone may cause pulmonary adverse reactions to raise clinical awareness, and for the first time indicates that hormone therapy is needed for patients whose eosinophils continue to increase after discontinuation.

The paradoxical role of transforming growth factor-ß in controlling oral squamous cell carcinoma development.

Transforming growth factor-ß (TGF-ß) is a multifunctional cytokine that plays a vital role in regulating cell growth, differentiation and survival in various tissues. It participates in a variety of cellular processes, including cell apoptosis, cell migration and evasion, and plays a paradoxical role in tumor genesis and development. In the early stage of tumor, TGF-ß inhibits the occurrence of tumor by inhibiting cell proliferation and regulating cell apoptosis. In the advanced stage of tumor, TGF-ß promotes tumor development and affects prognosis by promoting cell survival and proliferation, cell migration and invasion, participates in immune escape, etc. In this article, we will review the paradoxical role of TGF-ß on the occurrence and development of oral squamous cell carcinoma.

Comparative transcriptome analysis of Cyperus esculentus and C. rotundus with contrasting oil contents in tubers defines genes and regulatory networks involved in oil accumulation.

Plant vegetative organs present great potential for lipid storage, with tubers of Cyperus esculentus as a unique example. To investigate the genome and transcriptomic features of C. esculentus and related species, we sequenced and assembled the C. esculentus genome at the contig level. Through a comparative study of high-quality transcriptomes across 36 tissues from high-oil and intermediate-oil C. esculentus and low-oil Cyperus rotundus, we identified potential genes and regulatory networks related to tuber oil accumulation. First, we identified tuber-specific genes in two C. esculentus cultivars. Second, genes involved in fatty acid (FA) biosynthesis, triacylglycerol synthesis, and TAG packaging presented increased activity in the later stages of tuber development. Notably, tubers with high oil contents presented higher levels of these genes than those with intermediate oil contents did, whereas tubers with low oil contents presented minimal gene expression. Notably, a large fragment of the FA biosynthesis rate-limiting enzyme-encoding gene BCCP1 was missing from the C. rotundus transcript, which might be responsible for blocking FA biosynthesis in its tubers. WGCNA pinpointed a gene module linked to tuber oil accumulation, with a coexpression network involving the transcription factors WRI1, MYB4, and bHLH68. The ethylene-related genes in this module suggest a role for ethylene signaling in oil accumulation, which is supported by the finding that ethylene (ETH) treatment increases the oil content in C. esculentus tubers. This study identified potential genes and networks associated with tuber oil accumulation in C. esculentus, highlighting the role of specific genes, transcription factors, and ethylene signaling in this process.

Emerging connectivity of programmed cell death pathways and pulmonary vascular remodelling during pulmonary hypertension.

Pulmonary hypertension (PH) is a chronic progressive vascular disease characterized by abnormal pulmonary vascular resistance and pulmonary artery pressure. The major structural alteration during PH is pulmonary vascular remodelling, which is mainly caused by the imbalance between proliferation and apoptosis of pulmonary vascular cells. Previously, it was thought that apoptosis was the only type of programmed cell death (PCD). Soon afterward, other types of PCD have been identified, including autophagy, pyroptosis, ferroptosis and necroptosis. In this review, we summarize the role of the above five forms of PCD in mediating pulmonary vascular remodelling, and discuss their guiding significance for PH treatment. The current review could provide a better understanding of the correlation between PCD and pulmonary vascular remodelling, contributing to identify new PCD-associated drug targets for PH.

Ophiopogonin D' inhibited tumour growth and metastasis of anaplastic thyroid cancer by modulating JUN/RGS4 signalling.

Anaplastic thyroid cancer (ATC), an aggressive malignancy with virtually 100% disease-specific mortality, has long posed a formidable challenge in oncology due to its resistance to conventional treatments and the severe side effects associated with current regimens such as doxorubicin chemotherapy. Consequently, there was urgent need to identify novel candidate compounds that could provide innovative therapeutic strategies for ATC. Ophiopogonin D' (OPD'), a triterpenoid saponin extracted, yet its roles in ATC has not been reported. Our data demonstrated that OPD' potently inhibited proliferation and metastasis of ATC cells, promoting cell cycle arrest and apoptosis. Remarkably, OPD' impeded growth and metastasis of ATC in vitro and in vivo, displaying an encouraging safety profile. Regulator of G-protein signalling 4 (RGS4) expression was significantly up-regulated in ATC compared to normal tissues, and this upregulation was suppressed by OPD' treatment. Mechanistically, we elucidated that the transcription factor JUN bound to the RGS4 promoter, driving its transactivation. However, OPD' interacted with JUN, attenuating its transcriptional activity and thereby disrupting RGS4 overexpression. In summary, our research revealed that OPD' bound with JUN, which in turn resulted in the suppression of transcriptional activation of RGS4, thereby eliciting cell cycle arrest and apoptosis in ATC cells. These findings could offer promise in the development of high-quality candidate compounds for treatment in ATC.