Clinicopathological characteristics of secondary trigeminal neuralgia due to cerebellopontine angle tumors. / æ¡¥å°è„‘è§’è‚¿ç˜¤ç»§å‘æ€§ä¸‰å‰ç¥žç»ç—›çš„ä¸´åºŠç— ç†ç‰¹å¾.

OBJECTIVES: Cerebellopontine angle (CPA) tumors are a common cause of secondary trigeminal neuralgia (TN), characterized by their concealed location, slow progression, and difficulty in early detection. This study aims to explore the clinicopathological characteristics of patients with secondary TN due to CPA tumors to enhance understanding and management of secondary TN. METHODS: A retrospective analysis was conducted on clinical data and pathological results of 116 patients with CPA tumor-related TN treated at Xiangya Hospital of Central South University from January 1, 2017 to December 31, 2022. The study analyzed the relationship of tumor pathological types with clinical manifestations, tumor location, surgical methods, and treatment outcomes. RESULTS: Among the cases, 95.7% (111/116) were benign tumors, 3.4% (4/116) were malignant tumors, and 0.9% (1/116) were borderline tumors. Benign tumors were predominantly acoustic neuromas, meningiomas, and schwannomas. Among the patients, 46.6% (54/116) presented with isolated TN, while 53.4% (62/116) exhibited other associated symptoms depending on factors such as tumor growth location and rate. The complete resection rate in this group was over 90%, with 41.4% (48/116) of patients undergoing concurrent microvascular decompression after tumor resection, predominantly for schwannomas. The overall effective rate of surgical treatment reached 93.9%, with schwannomas showing higher efficacy rates compared with acoustic neuromas and meningiomas (P<0.05). The recurrence rate of acoustic neuromas was significantly higher than that of meningiomas and schwannomas (P<0.05). CONCLUSIONS: CPA tumors are a major cause of secondary TN, predominantly benign, with occasional underdiagnosed malignant tumors. Early diagnosis and treatment significantly impact prognosis. Different tumor types vary in clinical symptoms, surgical approaches, and treatment efficacy. Surgical strategies should balance tumor resection extent and neural function preservation, with microvascular decompression as necessary.

Impact of dietary n-6/n-3 fatty acid ratio of atherosclerosis risk: A review.

Atherosclerosis is a causative factor associated with cardiovascular disease (CVD). Over the past few decades, extensive research has been carried out on the relationship between the n-6/n-3 fatty acid ratio of ingested lipids and the progression of atherosclerosis. However, there are still many uncertainties regarding the precise nature of this relationship, which has led to challenges in providing sound dietary advice to the general public. There is therefore a pressing need to review our current understanding of the relationship between the dietary n-6/n-3 fatty acid ratio and atherosclerosis, and to summarize the underlying factors contributing to the current uncertainties. Initially, this article reviews the association between the n-6/n-3 fatty acid ratio and CVDs in different countries. A summary of the current understanding of the molecular mechanisms of n-6/n-3 fatty acid ratio on atherosclerosis is then given, including inflammatory responses, lipid metabolism, low-density lipoprotein cholesterol oxidation, and vascular function. Possible reasons behind the current controversies on the relationship between the n-6/n-3 fatty acid ratio and atherosclerosis are then provided, including the precise molecular structures of the fatty acids, diet-gene interactions, the role of fat-soluble phytochemicals, and the impact of other nutritional factors. An important objective of this article is to highlight areas where further research is needed to clarify the role of n-6/n-3 fatty acid ratio on atherosclerosis.

Molecular mechanism of renal lipid accumulation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.

Exploring the characteristics, digestion behaviors, and nutraceutical potential of the underutilized Chimonanthus praecox (L.) link kernel oil: A combined in vitro and in vivo study.

Chimonanthus praecox (L.) Link kernel oil (LMO) has the potential to expand the variety of nutraceutical plant oils available and provide support for the application of functional food. This study aimed to assess the edible potential of LMO by examining its physicochemical characteristics, digestion behaviors, and nutraceutical properties. The results revealed that LMO has a high oil content of 40.84% and is particularly rich in linoleic acid (53.37-56.30%), oleic acid (22.04-25.08%) and triacylglycerol (TAG) of linoleic acid -palmitoleic acid- oleic acid (10.57-12.70%). The quality characteristics and phytochemical composition of LMO were found to be influenced by variety and extraction methods used. In simulated in vitro digestion tests, LMO showed a better lipid release rate and degree. Animal studies further demonstrated that LMO led to better TAG and cholesterol excretion compared to soybean oil and camellia oleifera oil. Overall, this study highlights the potential of LMO as a high-quality edible oil.

Access to treatment before and after Medicare coverage of opioid treatment programs.

Since January 2020, Medicare has covered opioid use disorder (OUD) treatment services at opioid treatment programs (OTPs), the only outpatient settings allowed to dispense methadone for treating OUD. This study examined policy-associated changes in Medicare acceptance and the availability of four OUD treatment services (ongoing buprenorphine, HIV/AIDS education, employment services, and comprehensive mental health assessment), by for-profit status, and county-level changes in Medicare-accepting-OTPs access, by sociodemographic characteristics (racial composition, poverty rate, and rurality). Using data from the 2019-2022 National Directory of Drug and Alcohol Abuse Treatment Facilities, we found Medicare acceptance increased from 21.31% in 2018 to 80.76% in 2021. The availability of the four treatment services increased, but no increases were significantly associated with Medicare coverage. While county-level OTP access significantly improved, counties with higher rates of non-White residents experienced an additional average increase of 0.86 Medicare-accepting-OTPs (95% CI, 0.05-1.67) compared to those without higher rates of non-White populations. Overall, Medicare coverage was associated with improved OTP access, not ancillary services.

4,4-Dimethylsterols Reduces Fat Accumulation via Inhibiting Fatty Acid Amide Hydrolase In Vitro and In Vivo.

4,4-Dimethylsterols constitute a unique class of phytosterols responsible for regulating endogenous cannabinoid system (ECS) functions. However, precise mechanism through which 4,4-dimethylsterols affect fat metabolism and the linkage to the ECS remain unresolved. In this study, we identified that 4,4-dimethylsterols, distinct from 4-demethseterols, act as inhibitors of fatty acid amide hydrolases (FAAHs) both in vivo and in vitro. Genetic ablation of FAAHs (faah-1) abolishes the effects of 4,4-dimethylsterols on fat accumulation and locomotion behavior in a Caenorhabditis elegans model. We confirmed that dietary intervention with 4,4-dimethylsterols in a high-fat diet (HFD) mouse model leads to a significant reduction in body weight (>11.28%) with improved lipid profiles in the liver and adipose tissues and increased fecal triacylglycerol excretion. Untargeted and targeted metabolomics further verified that 4,4-dimethylsterols influence unsaturated fatty acid biosynthesis and elevate oleoyl ethanolamine levels in the intestine. We propose a potential molecular mechanism in which 4,4-dimethylsterols engage in binding interactions with the catalytic pocket (Ser241) of FAAH-1 protein due to the shielded polarity, arising from the presence of 2 additional methyl groups (CH3). Consequently, 4,4-dimethylsterols represent an unexplored class of beneficial phytosterols that coordinate with FAAH-1 activity to reduce fat accumulation, which offers new insight into intervention strategies for treating diet-induced obesity.

Cholesterol 25-Hydroxylase Protects Against Diabetic Kidney Disease by Regulating ADP Ribosylation Factor 4.

Cholesterol 25-hydroxylase (CH25H), an enzyme involved in cholesterol metabolism, regulates inflammatory responses and lipid metabolism. However, its role in kidney disease is not known.  The author found that CH25H transcript is expressed mostly in glomerular and peritubular endothelial cells and that its expression increased in human and mouse diabetic kidneys.  Global deletion of Ch25h in Leprdb/db mice aggravated diabetic kidney disease (DKD), which is associated with increased endothelial cell apoptosis. Treatment of 25-hydroxycholesterol (25-HC), the product of CH25H, alleviated kidney injury in Leprdb/db mice. Mechanistically, 25-HC binds to GTP-binding protein ADP-ribosylation factor 4 (ARF4), an essential protein required for maintaining protein transport in the Golgi apparatus. Interestingly, ARF4's GTPase-activating protein ASAP1 is also predominantly expressed in endothelial cells and its expression increased in DKD. Suppression of ARF4 activity by deleting ARF4 or overexpressing ASAP1 results in endothelial cell death. These results indicate that 25-HC binds ARF4 to inhibit its interaction with ASAP1, and thereby resulting in enhanced ARF4 activity to confer renoprotection. Therefore, treatment of 25-HC improves kidney injury in DKD in part by restoring ARF4 activity to maintain endothelial cell survival. This study provides a novel mechanism and a potential new therapy for DKD.

Robotic wireless capsule endoscopy: recent advances and upcoming technologies.

Wireless capsule endoscopy (WCE) offers a non-invasive evaluation of the digestive system, eliminating the need for sedation and the risks associated with conventional endoscopic procedures. Its significance lies in diagnosing gastrointestinal tissue irregularities, especially in the small intestine. However, existing commercial WCE devices face limitations, such as the absence of autonomous lesion detection and treatment capabilities. Recent advancements in micro-electromechanical fabrication and computational methods have led to extensive research in sophisticated technology integration into commercial capsule endoscopes, intending to supersede wired endoscopes. This Review discusses the future requirements for intelligent capsule robots, providing a comparative evaluation of various methods' merits and disadvantages, and highlighting recent developments in six technologies relevant to WCE. These include near-field wireless power transmission, magnetic field active drive, ultra-wideband/intrabody communication, hybrid localization, AI-based autonomous lesion detection, and magnetic-controlled diagnosis and treatment. Moreover, we explore the feasibility for future "capsule surgeons".

The impact of exercise on the gut microbiota in middle-aged amateur serious runners: a comparative study.

Introduction: Exercise, health, and the gut microbiota (GM) are strongly correlated. Research indicates that professional athletes, especially ultra-marathon runners, have unique GM characteristics. However, more research has focused on elite athletes, with little attention given to amateur sports enthusiasts, especially those in the middle-aged population. Therefore, this study focuses on the impact of long-term running on the composition and potential functions of the GM in middle-aged individuals. Methods: We compared the GM of 25 middle-aged serious runnerswith 22 sedentary healthy controls who had minimal exercise habitsusing 16S rRNA gene sequencing. Additionally, we assessed dietary habits using a food frequency questionnaire. Results and Discussion: Statistical analysis indicates that there is no significant difference in dietary patterns between the control group and serious runners. Diversity analysis results indicate that there is no significant difference in α diversity between the two groups of GM, but there is a significant difference in ß diversity. Analysis of the composition of GM reveals that Ruminococcus and Coprococcus are significantly enriched in serious runners, whereas Bacteroides, Lachnoclostridium, and Lachnospira are enriched in the control group. Differential analysis of functional pathway prediction results reveals significant differences in the functional metabolism levels of GM between serious runners and the control group. Further correlation analysis results indicate that this difference may be closely related to variations in GM. In conclusion, our results suggest that long-term exercise can lead to changes in the composition of the GM. These changes have the potential to impact the overall health of the individual by influencing metabolic regulation.

TransAC4C-a novel interpretable architecture for multi-species identification of N4-acetylcytidine sites in RNA with single-base resolution.

N4-acetylcytidine (ac4C) is a modification found in ribonucleic acid (RNA) related to diseases. Expensive and labor-intensive methods hindered the exploration of ac4C mechanisms and the development of specific anti-ac4C drugs. Therefore, an advanced prediction model for ac4C in RNA is urgently needed. Despite the construction of various prediction models, several limitations exist: (1) insufficient resolution at base level for ac4C sites; (2) lack of information on species other than Homo sapiens; (3) lack of information on RNA other than mRNA; and (4) lack of interpretation for each prediction. In light of these limitations, we have reconstructed the previous benchmark dataset and introduced a new dataset including balanced RNA sequences from multiple species and RNA types, while also providing base-level resolution for ac4C sites. Additionally, we have proposed a novel transformer-based architecture and pipeline for predicting ac4C sites, allowing for highly accurate predictions, visually interpretable results and no restrictions on the length of input RNA sequences. Statistically, our work has improved the accuracy of predicting specific ac4C sites in multiple species from less than 40% to around 85%, achieving a high AUC > 0.9. These results significantly surpass the performance of all existing models.

Performance-Based Hierarchical Fault-Tolerant Control for Closed-Loop Systems With Multiplicative Faults: A Data-Driven Design Method.

Fault-tolerant control (FTC) is vital for the safety and reliability of automatic systems. Most of the existing FTC methods are developed for open-loop systems subject to additive faults, regardless of the widely present control loops and multiplicative faults within systems. In this article, a performance-based FTC strategy is proposed for the closed-loop systems with multiplicative faults. Considering the high efforts in modeling complex systems, the proposed FTC strategy is realized in the data-driven context. Specifically, a nominal feedback-feedforward controller is first established for the fault-free systems. By selecting the system stability and reference tracking behavior as the key performance indices, two performance evaluators are constructed to detect and classify the occurred multiplicative faults based on the fault-induced effects on the system performance. Then, with the aid of the coprime factorization technique, the multiplicative faults, in the form of additive perturbations to the system coprime factors, are estimated utilizing the closed-loop process data. Furthermore, based on the fault knowledge, a hierarchical fault-tolerant tracking controller is developed according to the levels of system performance degradations, where the functional controller parameters are reconfigured with different priorities. Finally, case studies are provided to validate the effectiveness of the proposed method.

Functional prediction of the potential NGLY1 mutations associated with rare disease CDG.

Genetic diseases are currently diagnosed by functional mutations. However, only some mutations are associated with disease. It is necessary to establish a quick prediction model for clinical screening. Pathogenic mutations in NGLY1 cause a rare autosomal recessive disease known as congenital disorder of deglycosylation (NGLY1-CDDG). Although NGLY1-CDDG can be diagnosed through gene sequencing, clinical relevance of a detected mutation in NGLY1 needs to be further confirmed. In this study, taken NGLY1-CDDG as an example, a comprehensive and practical predictive model for pathogenic mutations on NGLY1 through an NGLY1/Glycopeptide complex model was constructed, the binding sites of NGLY1 and glycopeptides were simulated, and an in vitro enzymatic assay system was established to facilitate quick clinical decisions for NGLY1-CDDG patients. The docking model covers 42 % of reported NGLY1-CDDG missense mutations (5/12). All reported mutations were subjected to in vitro enzymatic assay in which 18 mutations were dysfunctional (18/30). In addition, a full spectrum of functional R328 mutations was assayed and 11 mutations were dysfunctional (11/19). In this study, a model of NGLY1 and glycopeptides was built for potential functional mutations in NGLY1. In addition, the effect of potential regulatory compounds, including N-acetyl-l-cysteine and dithiothreitol, on NGLY1 was examined. The established in vitro assay may serve as a standard protocol to facilitate rapid diagnosis of all mutations in NGLY1-CDDG. This method could also be applied as a comprehensive and practical predictive model for the other rare genetic diseases.

RNF166 promotes colorectal cancer progression by recognizing and destabilizing poly-ADP-ribosylated angiomotins.

Activation of the Hippo pathway by angiomotins to limit colorectal cancer progression is prevalent, whereas the regulation of angiomotins remains elusive. In this study, we uncover the involvement of an upregulated E3 ubiquitin ligase called RNF166, which destabilizes angiomotins, activates YAP, and is associated with a poor prognosis in colorectal cancer patients. Mechanistically, RNF166 specifically recognizes PARsylated angiomotin, a modification mediated by tankyrase at specific amino acid residues (D506, E513, E516, and E528). The tankyrase inhibitor XAV939, effectively prevents RNF166-dependent destabilization of angiomotins and subsequent activation of YAP. Additionally, YAP-5SA, a constitutively active form of YAP, rescues colorectal cancer progression following knockdown of RNF166. Importantly, the C-terminus of RNF66, particularly the Di19-ZF domain, is the crucial region responsible for recognizing ADP-ribosylated angiomotins. Together, this work not only sheds light on the regulation of the Hippo pathway in colorectal cancer but also uncovers a novel poly(ADP-ribose)-binding domain, which may serve as a potential therapeutic target for intervention.

External validation of the SYNTAX score II 2020 in patients with chronic renal insufficiency.

BACKGROUND: The SYNTAX score Ⅱ 2020 (SSⅡ-2020) was created as a customized decision-making tool for individuals diagnosed with complex coronary artery disease (CAD). Nevertheless, there has been a scarcity of research investigating the long-term predictive significance of SSⅡ-2020 for patients with both CAD and chronic renal insufficiency (CRI) who undergo percutaneous coronary intervention (PCI). AIMS: We sought to showcase the prognostic capacity of SSII-2020 in evaluating long-term all-cause mortality (ACM) within this high-risk patient cohort. METHODS: A retrospective cohort comprising 1156 individuals diagnosed with CRI and exhibiting left main CAD, three-vessel CAD or both was included in this investigation. We categorized participants into three groups based on the optimal SSII-2020 threshold for predicting long-term ACM, determined using the X-tile software. RESULTS: At the median follow-up duration of 6.3 years, the ACM rates were determined to be 10% in the low, 17% in the moderate, and 28% in the high SSII-2020 groups (p < 0.001). Employing multivariate Cox regression analysis, it was observed that the high SSII-2020 group exhibited a 3.289-fold increased risk of ACM (95% confidence interval [CI]: 2.229-4.856, p < 0.001) compared with the low SSII-2020 group, whereas the high SSII-2020 group displayed a 1.757-fold (95% CI: 1.190-2.597, p = 0.005) in comparison to the median SSII-2020 groups. Compared with SSII, the SSII-2020 had an incremental value for predicting 7-year ACM (C-index: 0.662 vs. 0.534, p = 0.007; IDI: 0.016, p < 0.001). CONCLUSIONS: SSII-2020 enhances long-term ACM prediction, facilitates improved risk stratification, and improves clinical utility for PCI patients with complex CAD and CRI.

Acer truncatum Bunge seed oil ameliorated oxaliplatin-induced demyelination by improving mitochondrial dysfunction via the Pink1/Parkin mitophagy pathway.

Dietary nutritional support for special populations is an effective and feasible method to improve the quality of life of patients and reduce medical pressure. Acer truncatum Bunge seed oil (ATSO) is widely recognized for its ability to promote nerve myelin regeneration. To evaluate the ameliorative effects of ATSO on chemotherapy-induced demyelination, a zebrafish model of chemotherapy-induced demyelination was established. The results showed that 100 µg mL-1 of ATSO reversed tail morphology damage, axon degeneration, touch response delay, ROS level upregulation and the expression of myelin basic protein decrease in chemotherapy-induced zebrafish. In addition, the expression of myelin markers (including sox10, krox20, and pmp22) in oxaliplatin-induced cells was markedly reversed by ATSO and its active components (gondoic acid, erucic acid, and nervonic acid). ATSO and its active components could reverse demyelination by ameliorating mitochondrial dysfunction. Conversely, linoleic acid and linolenic acid promoted demyelination by exacerbating mitochondrial dysfunction. Moreover, the Pink1/Parkin pathway was recognized as the main reason for ATSO and its active components improving mitochondrial function by activating mitophagy and restoring autophagic flow. Taken together, this study demonstrated that ATSO and its active components could be further developed as novel functional food ingredients to antagonize demyelination.

Antioxidant interaction between α-tocopherol and γ-oryzanol in HepG2 cells.

Minor constituents exhibit certain antioxidant interactions in vitro, and the effects in different media are different. However, it is not clear whether there are antioxidant interactions in cells after digestion and absorption. We utilized the cellular antioxidant evaluation model in HepG2 cells to study the antioxidant interaction between α-tocopherol and γ-oryzanol, and the interaction mechanism of a binary mixture was also illustrated. A cellular antioxidant assay (CAA) model and a combined index (CI) method were firstly used to explore the antioxidant activity and interaction of the binary mixture in HepG2 cells. The CAA value was positively correlated with the single addition concentration, while the results displayed a biphasic tendency with increasing concentrations of the binary mixture. The combination of TO11 (1 µg mL-1 α-tocopherol and 10 µg mL-1 γ-oryzanol) showed the greatest antioxidant activity and synergistic effect, and the maximum CAA value reached up to 94.84 ± 4.2. Then the mechanism of the synergistic antioxidant effect of the binary mixture was explained from three aspects including cellular uptake, intracellular reactive oxygen species (ROS) level and endogenous enzyme activity. The results demonstrated that the antioxidant interaction of the binary mixture in cells was related to cellular uptake of minor constituents, and the combination of TO11 exerted a synergistic effect by scavenging ROS and up-regulating glutathione peroxidase (GSH-Px) activity, resulting in the strongest cellular antioxidant activity. This study throws light on the nature of antioxidant interaction between minor constituents, which may contribute to the development of related functional foods and rational dietary collocation.

Identification of prognostic coagulation-related signatures in clear cell renal cell carcinoma through integrated multi-omics analysis and machine learning.

Clear cell renal cell carcinoma is a threat to public health with high morbidity and mortality. Clinical evidence has shown that cancer-associated thrombosis poses significant challenges to treatments, including drug resistance and difficulties in surgical decision-making in ccRCC. However, the coagulation pathway, one of the core mechanisms of cancer-associated thrombosis, recently found closely related to the tumor microenvironment and immune-related pathway, is rarely researched in ccRCC. Therefore, we integrated bulk RNA-seq data, DNA mutation and methylation data, single-cell data, and proteomic data to perform a comprehensive analysis of coagulation-related genes in ccRCC. First, we demonstrated the importance of the coagulation-related gene set by consensus clustering. Based on machine learning, we identified 5 coagulation signature genes and verified their clinical value in TCGA, ICGC, and E-MTAB-1980 databases. It's also demonstrated that the specific expression patterns of coagulation signature genes driven by CNV and methylation were closely correlated with pathways including apoptosis, immune infiltration, angiogenesis, and the construction of extracellular matrix. Moreover, we identified two types of tumor cells in single-cell data by machine learning, and the coagulation signature genes were differentially expressed in two types of tumor cells. Besides, the signature genes were proven to influence immune cells especially the differentiation of T cells. And their protein level was also validated.

A Natural Compound Containing a Disaccharide Structure of Glucose and Rhamnose Identified as Potential N-Glycanase 1 (NGLY1) Inhibitors.

N-glycanase 1 (NGLY1) is an essential enzyme involved in the deglycosylation of misfolded glycoproteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, which could hydrolyze N-glycan from N-glycoprotein or N-glycopeptide in the cytosol. Recent studies indicated that NGLY1 inhibition is a potential novel drug target for antiviral therapy. In this study, structure-based virtual analysis was applied to screen candidate NGLY1 inhibitors from 2960 natural compounds. Three natural compounds, Poliumoside, Soyasaponin Bb, and Saikosaponin B2 showed significantly inhibitory activity of NGLY1, isolated from traditional heat-clearing and detoxifying Chinese herbs. Furthermore, the core structural motif of the three NGLY1 inhibitors was a disaccharide structure with glucose and rhamnose, which might exert its action by binding to important active sites of NGLY1, such as Lys238 and Trp244. In traditional Chinese medicine, many compounds containing this disaccharide structure probably targeted NGLY1. This study unveiled the leading compound of NGLY1 inhibitors with its core structure, which could guide future drug development.

Interaction effect of type 2 diabetes mellitus and hypertension on left atrial function: a three-dimensional echocardiography study.

Background: Type 2 diabetes mellitus (T2DM) and hypertension (HT) often coexist and contribute to left atrial (LA) functional abnormalities. The aim of the present study was to explore whether there is a potential interaction effect between T2DM and HT on LA function. Methods: A total of 135 patients (45 with T2DM only, 45 with HT only, and 45 with both T2DM and HT) were enrolled and compared to 45 age- and sex-matched controls. LA volume fraction, including LA ejection fraction (LAEF), LA expansion index (LAEI), LA passive emptying fraction (LAPEF), and LA active emptying fraction (LAAEF), and strain parameters, including LA reservoir longitudinal strain (LASr), LA conduit longitudinal strain (LAScd), and LA contraction longitudinal strain (LASct), were obtained using three-dimensional echocardiography (3DE). Results: Patients with T2DM had significantly more impaired LA reservoir and conduit functions compared to those without T2DM (P<0.05), and patients with HT had a significantly more impaired LA reservoir function, conduit function, and booster pump function compared to those without HT (P<0.05). Two-way analysis of variance showed that there were significant additive interaction effects between T2DM and HT with respect to LASr (PT2DM + HT =0.002) and LAScd (PT2DM + HT =0.001). Generalized linear model demonstrated that T2DM + HT had a greater relative contribution than either T2DM or HT alone to the LA strain indexes, even after adjustment for other confounders (LASr, ßT2DM + HT =-3.931, 95% CI: -6.237 to -1.624, P=0.001; LAScd, ßT2DM + HT=-3.781, 95% CI: -5.653 to -1.908, P<0.001). Conclusions: Both T2DM and HT had an adverse effect on LA function. The coexistence of both conditions further impaired LA performance in an additive interaction fashion.

Identification of a Difluorinated Alkoxy Sulfonyl Chloride as a Novel Antitumor Agent for Hepatocellular Carcinoma through Activating Fumarate Hydratase Activity.

Fenofibrate is known as a lipid-lowering drug. Although previous studies have reported that fenofibrate exhibits potential antitumor activities, IC50 values of fenofibrate could be as high as 200 µM. Therefore, we investigated the antitumor activities of six synthesized fenofibrate derivatives. We discovered that one compound, SIOC-XJC-SF02, showed significant antiproliferative activity on human hepatocellular carcinoma (HCC) HCCLM3 cells and HepG2 cells (the IC50 values were 4.011 µM and 10.908 µM, respectively). We also found this compound could inhibit the migration of human HCC cells. Transmission electron microscope and flow cytometry assays demonstrated that this compound could induce apoptosis of human HCC cells. The potential binding sites of this compound acting on human HCC cells were identified by mass spectrometry-cellular thermal shift assay (MS-CETSA). Molecular docking, Western blot, and enzyme activity assay-validated binding sites in human HCC cells. The results showed that fumarate hydratase may be a potential binding site of this compound, exerting antitumor effects. A xenograft model in nude mice demonstrated the anti-liver cancer activity and the mechanism of action of this compound. These findings indicated that the antitumor effect of this compound may act via activating fumarate hydratase, and this compound may be a promising antitumor candidate for further investigation.