Neutrophils in pancreatic ductal adenocarcinoma: bridging preclinical insights to clinical prospects for improved therapeutic strategies.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a dismal five-year survival rate of less than 10%. Neutrophils are key components of the innate immune system, playing a pivotal role in the PDAC immune microenvironment. AREAS COVERED: This review provides a comprehensive survey of the pivotal involvement of neutrophils in the tumorigenesis and progression of PDAC. Furthermore, it synthesizes preclinical and clinical explorations aimed at targeting neutrophils within the milieu of PDAC, subsequently proposing a conceptual framework to propel further inquiry focused on enhancing the therapeutic efficacy of PDAC through neutrophil-targeted strategies. PubMed and Web of Science databases were utilized for researching neutrophils in pancreatic cancer publications prior to 2024. EXPERT OPINION: Neutrophils play roles in promoting tumor growth and metastasis in PDAC and are associated with poor prognosis. However, the heterogeneity and plasticity of neutrophils and their complex relationships with other immune cells and extracellular matrix also provide new insights for immunotherapy targeting neutrophils to achieve a better prognosis for PDAC.

Proteomics Study of Benzene Metabolite Hydroquinone Induced Hematotoxicity in K562 Cells.

Objective: Hydroquinone (HQ), one of the phenolic metabolites of benzene, is widely recognized as an important participant in benzene-induced hematotoxicity. However, there are few relevant proteomics in HQ-induced hematotoxicity and the mechanism hasn't been fully understood yet. Methods: In this study, we treated K562 cells with 40 µmol/L HQ for 72 h, examined and validated protein expression changes by Label-free proteomic analysis and Parallel reaction monitoring (PRM), and performed bioinformatics analysis to identify interaction networks. Results: One hundred and eighty-seven upregulated differentially expressed proteins (DEPs) and 279 downregulated DEPs were identified in HQ-exposed K562 cells, which were involved in neutrophil-mediated immunity, blood microparticle, and other GO terms, as well as the lysosome, metabolic, cell cycle, and cellular senescence-related pathways. Focusing on the 23 DEGs and 5 DEPs in erythroid differentiation-related pathways, we constructed the network of protein interactions and determined 6 DEPs (STAT1, STAT3, CASP3, KIT, STAT5B, and VEGFA) as main hub proteins with the most interactions, among which STATs made a central impact and may be potential biomarkers of HQ-induced hematotoxicity. Conclusion: Our work reinforced the use of proteomics and bioinformatic approaches to advance knowledge on molecular mechanisms of HQ-induced hematotoxicity at the protein level and provide a valuable basis for further clarification.

Preliminary exploration of animal models of congenital choledochal cysts.

BACKGROUND: Various animal models have been used to explore the pathogenesis of choledochal cysts (CCs), but with little convincing results. Current surgical techniques can achieve satisfactory outcomes for treatment of CCs. Consequently, recent studies have focused more on clinical issues rather than basic research. Therefore, we need appropriate animal models to further basic research. AIM: To establish an appropriate animal model that may contribute to the investigation of the pathogenesis of CCs. METHODS: Eighty-four specific pathogen-free female Sprague-Dawley rats were randomly allocated to a surgical group, sham surgical group, or control group. A rat model of CC was established by partial ligation of the bile duct. The reliability of the model was confirmed by measurements of serum biochemical indices, morphology of common bile ducts of the rats as well as molecular biology experiments in rat and human tissues. RESULTS: Dilation classified as mild (diameter, ≥ 1 mm to < 3 mm), moderate (≥ 3 mm to < 10 mm), and severe (≥ 10 mm) was observed in 17, 17, and 2 rats in the surgical group, respectively, while no dilation was observed in the control and sham surgical groups. Serum levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, and total bile acids were significantly elevated in the surgical group as compared to the control group 7 d after surgery, while direct bilirubin, total bilirubin, and gamma-glutamyltransferase were further increased 14 d after surgery. Most of the biochemical indices gradually decreased to normal ranges 28 d after surgery. The protein expression trend of signal transducer and activator of transcription 3 in rat model was consistent with the human CC tissues. CONCLUSION: The model of partial ligation of the bile duct of juvenile rats could morphologically simulate the cystic or fusiform CC, which may contribute to investigating the pathogenesis of CC.

Clinical characteristics of choledochal cysts with intrahepatic bile duct dilatations: an observational study.

Purpose: Whether a dilated intrahepatic bile duct (IHBD) has any effect on the prognosis of choledochal cyst (CC) remains controversial. We aimed to summarize the clinical characteristics and prognosis of CC with IHBD dilatation. Methods: One hundred ninety-two children diagnosed with CC were identified, including 127 without IHBD dilatation (group A) and 65 with IHBD dilatation (group B). A retrospective analysis was performed to explore the clinical characteristics and prognosis of CC with IHBD dilatation based on clinical indices, symptoms, and complications. Results: Compared with group A, incidences of jaundice and fever were higher in group B (P = 0.010 and P = 0.033). Preoperative total bilirubin, direct bilirubin, and indirect bilirubin were increased in group B compared to group A (P = 0.005, P < 0.001, and P = 0.014), as were preoperative ALT, AST, γ-GT, and total bile acid (P = 0.006, P = 0.025, P < 0.001, and P = 0.024). The risk of liver fibrosis or cirrhosis was significantly increased for group B compared with group A (P = 0.012) and also occurred earlier in group B (P = 0.006). In the dilated IHBDs, 95.4% (62 of 65) recovered to normal, and more than half of dilated IHBDs (37 of 65) recovered to normal in 1 week. Conclusion: Most IHBDs can recover to normal postoperatively in a short time, and proactive treatment is recommended for CC patients with IHBD dilatation for significant abnormal liver functions.

RNF31 alleviates liver steatosis by promoting p53/BNIP3-related mitophagy in hepatocytes.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is one of the liver illnesses that may be affected by mitophagy, which is the selective removal of damaged mitochondria. RNF31, an E3 ubiquitin ligase, is carcinogenic in many malignancies. However, the influence of RNF31 on mitochondrial homeostasis and NAFLD development remains unknown. METHODS: Oleic-palmitic acid treated hepatocytes and high-fat diet (HFD)-fed mice were established to observe the effect of RNF31 on hepatocyte mitophagy and steatosis. Mitophagy processes were comprehensively assessed by mt-Keima fluorescence imaging, while global changes in hepatic gene expression were measured by RNA-seq. RESULTS: The present study discovered a reduction in RNF31 expression in lipotoxic hepatocytes with mitochondrial dysfunction. The observed decrease in RNF31 expression was associated with reduced mitochondrial membrane potential, disturbed mitophagy, and increased steatosis. Additionally, the findings indicated that RNF31 is a pivotal factor in the initiation of mitophagy and the facilitation of mitochondrial homeostasis, resulting in a decrease in steatosis in lipotoxic hepatocytes. Mechanistically, RNF31 enhanced p53 ubiquitination and subsequent proteasomal degradation. Down-regulation of p53 led to increased expression of the mitophagy receptor protein BCL2 and adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), thereby promoting mitophagy in hepatocytes. Furthermore, it was demonstrated that the transportation of RNF31 via small extracellular vesicles derived from mesenchymal stem cells (referred to as sEV) had a substantial influence on reducing hepatic steatosis and restoring liver function in HFD-fed mice. CONCLUSIONS: The findings highlight RNF31's essential role in the regulation of mitochondrial homeostasis in hepatocytes, emphasizing its potential as a therapeutic target for NAFLD.

Clinical Outcomes of Severe Rhinosinusitis Complicated with Cavernous Sinus Syndrome.

Background: Various diseases involving the cavernous sinus can cause a condition called cavernous sinus syndrome (CSS), which is characterized by ophthalmoplegia or sensory deficits over the face resulting from the compression effect of internal structure. While tumor compression is the most reported cause of CSS, statistical data on CSS caused by infections are limited. Its risk factors, treatment methods, and clinical outcomes are not well-documented. Methods: In this retrospective study, we reviewed the data of patients admitted to a tertiary medical center from 2015 to 2022 with a diagnosis of acute and chronic sinusitis and at least one diagnostic code for CSS symptoms. We manually reviewed whether patients were involved in two or more of the following cranial nerves (CN): CN III, CN IV, CN V, or CN VI, or at least one of these nerves with a neuroimaging-confirmed lesion in the cavernous sinus. Results: Nine patients were diagnosed with rhinosinusitis-related CSS. The most common comorbidity was type 2 diabetes, and the most common clinical manifestations were diplopia and blurred vision. The sphenoid sinus was the most affected sinus. One patient expired due to a severe brain abscess infection without surgery. The remaining patients underwent functional endoscopic sinus surgery, and 50% of the pathology reports indicated fungal infections. Staphylococcus spp. was the most cultured bacteria, and Amoxycillin/Clavulanate was the most used antibiotic. Only four patients had total recovery during the follow-up one year later. Conclusions: CSS is a rare but serious complication of rhinosinusitis. Patients with diabetes and the elderly may be at a higher risk for this complication. Even after treatment, some patients may still have neurological symptoms.

Deciphering the Synthetic and Refolding Strategy of a Cysteine-Rich Domain in the Tumor Necrosis Factor Receptor (TNF-R) for Racemic Crystallography Analysis and d-Peptide Ligand Discovery.

Many cell-surface receptors are promising targets for chemical synthesis because of their critical roles in disease development. This synthetic approach enables investigations by racemic protein crystallography and ligand discovery by mirror-image methodologies. However, due to their complex nature, the chemical synthesis of a receptor can be a significant challenge. Here, we describe the chemical synthesis and folding of a central, cysteine-rich domain of the cell-surface receptor tumor necrosis factor 1 which is integral to binding of the cytokine TNF-α, namely, TNFR-1 CRD2. Racemic protein crystallography at 1.4 Å confirmed that the native binding conformation was preserved, and TNFR-1 CRD2 maintained its capacity to bind to TNF-α (KD ≈ 7 nM). Encouraged by this discovery, we carried out mirror-image phage display using the enantiomeric receptor mimic and identified a d-peptide ligand for TNFR-1 CRD2 (KD = 1 µM). This work demonstrated that cysteine-rich domains, including the central domains, can be chemically synthesized and used as mimics for investigations.

Off-hours Surgery and Mortality in Patients With Type A Aortic Dissection Repair: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: The impact of off-hours admission (such as weekends, nighttime, and non-working hours) vs. regular hours (weekdays and daytime working hours) on the mortality risk of patients undergoing surgery for type A aortic dissection (TAAD) repair is still uncertain. To address this uncertainty, we undertook a comprehensive systematic review and meta-analysis. We aimed to assess the potential link between off-hours admission and the risk of mortality in patients undergoing TAAD repair surgery. METHODS: We conducted a thorough search of the PubMed, Embase, and Cochrane Library databases, covering the period from their inception to May 20, 2023. Our inclusion criteria encompassed all studies that examined the potential relationship between off-hour admission and mortality in individuals who had undergone surgery for TAAD repair. The odds ratios (ORs) were extracted and combined utilizing a random effects model for our synthesis. RESULTS: Nine studies with 16,501 patients undergoing TAAD repair surgery were included in the meta-analysis. Overall, patients who underwent surgery during the weekend had higher in-hospital mortality (pooled OR, 1.41; 95% confidence interval [CI], 1.14-1.75; p=0.002) than those treated on weekdays. However, the mortality risks among patients who underwent TAAD surgery during nighttime and non-working hours were not significantly elevated compared to daytime and working hours admission. CONCLUSIONS: Weekend surgery for TAAD was associated with a higher in-hospital mortality risk than weekday surgery. However, further studies are warranted to identify and develop strategies to improve the quality of round-the-clock care for patients with TAAD.

[Application and efficacy analysis of tympanic cartilage shaping device in endoscopic type â tympanoplasty].

Objective:To study the feasibility and efficacy of using a tympanic cartilage shaping device in endoscopic type Ⅰ tympanoplasty. Methods:A tympanic cartilage shaper was designed and manufactured by measuring tympanic membrane dimensions with HRCT imaging for cutting and shaping cartilage to repair the tympanic membrane. From August 2019 to October 2021, 66 patients（72 ears） with chronic suppurative otitis media in Xiangya Hospital underwent endoscopic type Ⅰ tympanoplasty with this tympanic cartilage shaping device, and were observed the tympanic membrane healing and hearing recovery effect after surgery. Postoperative follow-up ranged from 3-24 months, with an average of 9 months. The data were analyzed by the SPSS 26.0 software. Results:According to the imaging measurements, tympanic pars tensa width（8.60±0.20） mm, height（8.64±0.19） mm, design and manufacture a cylindrical cartilage shaping device with inner diameter 8.60 mm. After tympanoplasty, the healing rate of tympanic membrane was 100%; The average air-bone gap before surgery was（23.10±7.33） dB, then（14.30±6.40） dB 1 month after surgery, which were significant reduced compared with those before surgery. The average air-bone gap was（14.30±6.40） dB 3 month after surgery compared with 1 month after surgery, the difference was also statistically significant（t=6.630, P<0.05）. Conclusion:The tympanic membrane cartilage shaper shaping cartilage in endoscopic tympanoplasty is simple, stable and reliable, which can reduce the time of graft cartilage processing, improve the efficiency of surgery, and restore the tympanic membrane morphology and function in the postoperative period.

The Effect of Ciprofol on Postoperative Delirium in Elderly Patients Undergoing Thoracoscopic Surgery for Lung Cancer: A Prospective, Randomized, Controlled Trial.

Purpose: This study was conducted to assess whether ciprofol vs propofol could affect the incidence of postoperative delirium (POD) in elderly patients with lung cancer after thoracoscopic surgery. Patients and Methods: In this study, a total of 84 elderly patients undergoing thoracoscopic surgery for lung cancer were recruited and randomized into two groups to receive anesthesia with either ciprofol or propofol. The primary outcome was the incidence of POD within three days after surgery. Secondary outcomes included the Confusion Assessment Method (CAM) score, intraoperative indicators related to mean arterial pressure (MAP), and cerebral tissue oxygen saturation (SctO2). Moreover, MAP- and SctO2-related indicators associated with POD were analyzed. Results: The incidence of POD was 7.1% and 16.7%, respectively, in the ciprofol group and the propofol group (risk ratio [RR], 0.37; 95% confidence interval [CI], 0.07 to 2.03; risk difference [RD], -9.6%; 95% CI, -23.3% to 4.1%; p = 0.178). Compared with those in the propofol group, patients in the ciprofol group had lower CAM scores three days after surgery (13 (12, 15) vs 15 (14, 17); 12 (11, 13) vs 14 (13, 16); 12 (11, 12) vs 13 (12, 14), p<0.05). Besides, patients in the ciprofol group exhibited higher mean and minimum MAP (88.63 ± 6.7 vs 85 ± 8.3; 69.81 ± 9.59 vs 64.9 ± 9.43, p<0.05) and SctO2 (77.26 ± 3.96 vs 75.3 ± 4.49, 71.69 ± 4.51 vs 68.77 ± 6.46, p<0.05) and percentage of time for blood pressure stabilization (0.6 ± 0.14 vs 0.45 ± 0.14, p<0.05) than those in the propofol group. Furthermore, MAP and SctO2-related indicators were validated to correlate with POD. Conclusion: Anesthesia with ciprofol did not increase the incidence of POD compared with propofol. The results demonstrated that ciprofol could improve intraoperative MAP and SctO2 levels and diminish postoperative CAM scores.

Human leukocyte antigen class I antibody-activated endothelium promotes CD206+ M2 macrophage polarization and MMP9 secretion through TLR4 signaling and P-selectin in a model of antibody-mediated rejection and allograft vasculopathy.

HLA donor-specific antibodies (DSA) elicit alloimmune responses against the graft vasculature, leading to endothelial cell (EC) activation and monocyte infiltration during antibody-mediated rejection (AMR). AMR promotes chronic inflammation and remodeling, leading to thickening of the arterial intima termed transplant vasculopathy or cardiac allograft vasculopathy (CAV) in heart transplants. Intragraft-recipient macrophages serve as a diagnostic marker in AMR; however, their polarization and function remain unclear. In this study, we utilized an in vitro Transwell coculture system to explore the mechanisms of monocyte-to-macrophage polarization induced by HLA I DSA-activated ECs. Anti-HLA I (IgG or F(ab')2) antibody-activated ECs induced the polarization of M2 macrophages with increased CD206 expression and MMP9 secretion. However, inhibition of TLR4 signaling or PSGL-1-P-selectin interactions significantly decreased both CD206 and MMP9. Monocyte adherence to Fc-P-selectin coated plates induced M2 macrophages with increased CD206 and MMP9. Moreover, Fc-receptor and IgG interactions synergistically enhanced active-MMP9 in conjunction with P-selectin. Transcriptomic analysis of arteries from DSA+CAV+ rejected cardiac allografts and multiplex-immunofluorescent staining illustrated the expression of CD68+CD206+CD163+MMP9+ M2 macrophages within the neointima of CAV-affected lesions. These findings reveal a novel mechanism linking HLA I antibody-activated endothelium to the generation of M2 macrophages which secrete vascular remodeling proteins contributing to AMR and CAV pathogenesis.

Robotic-Assisted and Laparoscopic Splenectomy in Children: A Single Center Comparative Study.

Background: To explore the safety, efficacy, advantages, and disadvantages of robotic-assisted splenectomy (RS) in children by analyzing and comparing the clinical data of RS and laparoscopic splenectomy (LS). Methods: The clinical data of 35 children who underwent laparoscopic or RS or partial splenectomy from February 2010 to October 2022 were included. A retrospective analysis based on general information, clinical data, and prognosis were performed. Results: Among 35 cases, 14 cases, and 21 cases underwent RS and LS, respectively. The average operation time was 167 (120-224) minutes in the RS group and 176 (166-188) minutes in the LS group. The intraoperative blood loss was significantly larger in LS group than RS group (P = .0009). The length of hospital stay was significantly longer in LS group than RS group (P = .0015), and the hospitalization cost was significantly higher in RS group than LS group (P < .0001). There were no cases of conversion to laparotomy in the RS group, but two cases in the LS group. In terms of postoperative complications, there were one and three cases in the RS and LS groups, respectively. Conclusion: The Robotic Surgical System was safe and feasible in pediatric splenectomy or partial splenectomy which was an alternative to laparoscopic surgery.

[Corrigendum] Propofol­induced HOXA11­AS promotes proliferation, migration and invasion, but inhibits apoptosis in hepatocellular carcinoma cells by targeting miR­4458.

Following the publication of the above article, an interested reader drew to the authors' attention that the western blots for the PCNA and cyclin D1 bands appeared to be strikingly similar. The authors were able to re­examine their original data, and recognize how the error was made with respect to the compilation of this figure (they were also able to demonstrate to the Editorial Office how the error occurred). The revised version of Fig. 3, now incorporating the correct data for the PCNA bands in Fig. 3A, is shown on the next page. The authors can confirm that the errors associated with this figure did not have a significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 46: 1135­1145, 2020; DOI: 10.3892/ijmm.2020.4667].

TC2N inhibits distant metastasis and stemness of breast cancer via blocking fatty acid synthesis.

BACKGROUND: Tandem C2 domains, nuclear (TC2N) is a C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previously, we preliminarily reported that TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (BC) cells. Beyond that, its precise biological functions and detailed molecular mechanisms in BC development and progression are not fully understood. METHODS: Tumor tissues of 212 BC patients were subjected to tissue microarray and further assessed the associations of TC2N expression with pathological parameters and FASN expression. The protein levels of TC2N and FASN in cell lines and tumor specimens were monitored by qRT-PCR, WB, immunofluorescence and immunohistochemistry. In vitro cell assays, in vivo nude mice model was used to assess the effect of TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics, proteomics and lipidomics, and the underlying mechanism was explored by WB and co-IP assays. RESULTS: Here, we found that the expression of TC2N remarkedly silenced in metastatic and poorly differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem-like properties of BC via inhibition of fatty acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2B domain is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by competing with neddylated PTEN for binding to FASN in nucleus. On the other hand, cytoplasmic TC2N interacts with import proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level. CONCLUSIONS: Altogether, we demonstrate a previously unidentified role and mechanism of TC2N in regulation of lipid metabolism and PTEN neddylation, providing a potential therapeutic target for anti-cancer.

Multi-omics comprehensive analyses of programmed cell death patterns to regulate the immune characteristics of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous cancer with high morbidity and mortality. Triggering the programmed cell death (PCD) to enhance the anti-tumor therapies is being applied in multiple cancers. However, the limited understanding of genetic heterogeneity in HNSCC severely hampers the clinical efficacy. We systematically analyzed 14 types of PCD in HNSCC from The Cancer Genome Atlas (TCGA). We utilized ssGSEA to calculate the PCD scores and classify patients into two clusters. Subsequently, we displayed the genomic alteration landscape to unravel the significant differences in copy number alterations and gene mutations. Furthermore, we calculated the IC50 values of targeted drugs to predict the differences in sensitivity. To identify the immune-related prognostic types, we comprehensively estimated the relationship between immune indicators and all prognostic PCD in three datasets (TCGA, GSE65858, GSE41613). Finally, 7 regulators were filtered. Subsequently, we integrated 10 machine learning algorithms and 101 algorithm combinations to test the clinical predictive efficacy. Using WGCNA as a basis, we built a weighted co-expression network to identify modules involved in the immune landscape with different colors. Meanwhile, our results indicated that blue and red modules containing crucial regulators closely related to the CD4+, CD8+ T cells, TMB or PD-L1. FCGR2A from blue module, CSF2, INHBA, and THBS1 from the red module were determined. After verifying in vivo experiments, FCGR2A was identified as hub gene. In conclusion, our findings suggest a potential role of PCD in HNSCC, offering new insights into effective immunotherapy and anti-tumor therapies in HNSCC.

The Efficacy of Magnesium Sulfate (MgSO4) Wet Dressing in Reducing Eyelid Swelling and Bruising after Blepharoplasty: A Randomized, Controlled, and Observer-Blinded Assessment Study.

The purpose of this study was to evaluate the effects of wet dressing with 50% magnesium sulfate (MgSO4) solution on decreasing eyelid swelling and bruising after blepharoplasty. Fifty-eight patients (23 male and 35 female) who underwent bilateral blepharoplasty were enrolled in our randomized clinical trial. One side of the periorbital area (upper and lower eyelids) per patient received a wet dressing with 50% MgSO4 solution randomly, and the other side was cooled with an ice pack from the first postoperative day for two consecutive days (30 minutes per time and twice a day). The eyelid edema and ecchymosis were evaluated and classified using respective graded scales. Degrees of eyelid edema were similar after surgery in both groups (p > 0.05) and were significantly decreased with time. Compared with the cooled ones, less swelling was observed in the eyelids treated by MgSO4 wet compress on postoperative day 5 (p < 0.01). Both the incidence and area of ecchymosis were lower in the MgSO4 group than those in the cooling group (p < 0.01 and p < 0.05, respectively). Moreover, the majority of patients (39/58, 67.2%) indicated a preference for MgSO4 wet dressing over ice cooling. MgSO4 wet dressing can be conveniently applied to alleviate eyelid swelling and reduce recovery time after blepharoplasty.

Syntheses of the ω-pyridinium-containing very-long-chain ceramides PyrCer(24:1(15Z)) and PyrCer(24:0) and their anticancer activity.

Ceramides, crucial sphingolipids in cellular biology, play various roles ranging from structural membrane integrity to signaling pathway regulation. Structurally, a ceramide consists of a fatty acid connected to a sphingoid base. The characteristics of the fatty acid chain, including length and saturation, determine the physiological properties of the ceramide. Ceramides typically fall into the following categories based on chain length: medium, long, very-long, and ultra-long. Among them, two very-long-chain ceramides, Cer(24:1(15Z)) and Cer(24:0), have been extensively studied, and they are known for their regulatory functions. However, the hydrophobic natures of ceramides, arising from their long hydrocarbon chain impedes their solubilities and levels of cellular delivery. Although ω-pyridinium ceramide analogs (ω-PyrCers) have been developed to address this issue, ω-PyrCers with very-long fatty acid chains or unsaturation have not been developed, presumably due to limited access to the corresponding ω-bromo fatty acids required in their syntheses. In this study, we prepared the ω-PyrCers of Cer(24:1(15Z)) and Cer(24:0), PyrCer(24:1(15Z)) and PyrCer(24:0), respectively. The key in the synthesis is the Wittig reaction to prepare the ω-bromo fatty acid with an appropriate chain length and (Z)-double bond position. Preliminary evaluation of the PyrCer(24:1(15Z)) and PyrCer(24:0) revealed their potential in hepatocellular carcinoma treatment.

Associations of serum gamma-linolenic acid levels with erythema severity and anxiety/depression status in patients with rosacea.

BACKGROUND: The development of rosacea is suggested to be closely associated with lipid metabolism, inflammation, and anxiety/depression. Gamma linolenic acid (GLA) is a key factor participating in lipid metabolism, which is also confirmed to regulate the inflammatory response. However, the associations of serum GLA levels with rosacea severity and psychological status still remain unclear. OBJECTIVE AND LIMITATIONS OF THE STUDY: The present study aimed to investigate the associations of gamma linolenic acid (GLA), a key factor participating in lipid metabolism and the inflammatory response, with rosacea severity and psychological status. The present study still had some limitations. First, this study is a cross-sectional study and does not provide longitudinal evidence about the relationship between GLA and rosacea; Second, the cohort in this study is also relatively small, and a larger cohort is needed in further investigation to reveal the potential role of lipid metabolism in the pathogenesis of rosacea. METHODS: A total of 62 rosacea patients were consecutively recruited. Patient's Self-Assessment (PSA) scale and Clinician Erythema Assessment (CEA) as well as 7-item Generalized Anxiety Disorder (GAD-7) and 9-item Patient Health Questionnaire (PHQ-9) were conducted to evaluate the degree of erythema severity and anxiety/depression, respectively. Serum GLA levels were determined by gas chromatography mass. RESULTS: Lower levels of serum GLA in rosacea patients were observed (p<0.001), and subgroup analysis revealed that patients with higher-level GLA had lower scores of PSA, CEA, GAD-7 and PHQ-9. Moreover, Spearman correlation analysis uncovered that serum GLA levels were negatively associated with PSA, CEA, GAD-7 as well and PHQ-9 scores, respectively. Linear regression model found that serum GLA levels at baseline were a predictive factor for prognosis of clinical outcomes after 1-month conventional treatment. CONCLUSION: The present study indicates that lower levels of serum GLA in rosacea patients are negatively associated with the degree of erythema and anxiety/depression status.

Protective effect of novel angiotensin receptor neprilysin inhibitor S086 on target organ injury in spontaneously hypertensive rats.

BACKGROUND: Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure associated with injury to the heart, kidney, brain, and other organs. Angiotensin receptor neprilysin inhibitors (ARNi), including angiotensin receptor blockers (ARBs) and neprilysin inhibitors (NEPi), have been shown to be safe and effective at reducing blood pressure and alleviating development of target organ injury. This study was used to develop S086 as a novel ARNi and conducted preclinical studies in animal models to evaluate the protective effects of S086 on target organs. METHODS: This study used a 14-month-old spontaneously hypertensive rat (SHR) model to evaluate the protective effects of S086 on the cardiovascular system and organs such as heart and kidney by blood pressure monitoring, urine and blood examination, pathological examination, and immunological index detection. RESULTS: After administering S086 orally to the SHR, their blood pressure and levels of renal injury indicators such as serum creatinine and urinary microalbumin were reduced, and myocardial cell necrosis and cardiac fibrosis of the heart were significantly improved. In addition, there were also significantly improvements in the histological lesions of blood vessels and the kidneys. CONCLUSIONS: The findings showed that S086 effectively reduced the blood pressure of SHR and had effects on alleviating development of heart, blood vessels and kidney.