Apigenin Suppresses MED28-Mediated Cell Growth in Human Liver Cancer Cells.

Flavonoids exhibit health-promoting benefits against multiple chronic diseases, including cancer. Apigenin (4',5,7-trihydroxyflavone), one flavonoid present in fruits and vegetables, is potentially applicable to chemoprevention. Despite considerable progress in the therapeutic regimen of liver cancer, its prognosis remains poor. MED28, a Mediator subunit for transcriptional activation, is implicated in the development of several types of malignancy; however, its role in liver cancer is unknown at present. In liver cancer, the AKT/mammalian target of rapamycin (mTOR) is one major pathway involved in the oncogenic process. The aim of this study is to investigate the role of apigenin and MED28 in AKT/mTOR signaling in liver cancer. We first identified a connectivity score of 92.77 between apigenin treatment and MED28 knockdown in several cancer cell lines using CLUE, a cloud-based software platform to assess connectivity among compounds and genetic perturbagens. Higher expression of MED28 predicted a poorer survival prognosis; MED28 expression in liver cancer tissue was significantly higher than that of normal tissue, and it was positively correlated with tumor stage and grade in The Cancer Genome Atlas Liver Cancer (TCGA-LIHC) data set. Knockdown of MED28 induced cell cycle arrest and suppressed the AKT/mTOR signaling in two human liver cancer cell lines, HepG2 and Huh 7, accompanied by less lipid accumulation and lower expression and nuclear localization of sterol regulatory element binding protein 1 (SREBP1). Apigenin inhibited the expression of MED28, and the effect of apigenin mimicked that of the MED28 knockdown. On the other hand, the AKT/mTOR signaling was upregulated when MED28 was overexpressed. These data indicated that MED28 was associated with the survival prognosis and the progression of liver cancer by regulating AKT/mTOR signaling and apigenin appeared to inhibit cell growth through MED28-mediated mTOR signaling, which may be applicable as an adjuvant of chemotherapy or chemoprevention in liver cancer.

Timing of decompression in central cord syndrome: a systematic review and meta-analysis.

PURPOSE: This study compared the recovery of motor function and the safety of early and delayed surgical intervention in patients with central cord syndrome (CCS). METHODS: PubMed, Embase, Cochrane Library, and Web of Science were employed to retrieve the targeted studies published from inception to February 19, 2023. Comparative studies of early versus delayed surgical decompression in CCS based on American Spinal Injury Association motor score (AMS) recovery, complication rates, and mortality were selected. The statistical analyses were performed using STATA 16.0 and RevMan 5.4. RESULTS: Our meta-analysis included 13 studies comprising 8424 patients. Results revealed that early surgery improved AMS scores significantly compared with delayed surgery, with an increase in MDs by 7.22 points (95% CI 1.98-12.45; P = 0.007). Additionally, early surgery reduced the complication rates than delayed surgery (OR 0.53, 95% CI 0.42-0.67, P < 0.00001). However, no significant difference was observed in mortality between the two groups (OR 0.97; 95% CI 0.75-1.26; P = 0.84). CONCLUSIONS: Early surgical decompression for CCS can improve motor function and reduce the incidence of complications without affecting the mortality rate in patients. Future research should focus on investigating and analyzing the optimal window period for early CCS surgery. Additionally, the timing of surgery should be determined based on the patient's condition and available medical resources.

Dynamic change of metabolic dysfunction-associated steatotic liver disease in patients with hepatitis C virus infection after achieving sustained virologic response with direct-acting antivirals.

BACKGROUND: Information on the dynamics of metabolic dysfunction-associated steatotic liver disease (MASLD) among hepatitis C virus patients achieving sustained virologic response (SVR12) with direct-acting antivirals (DAAs) is limited. METHODS: We enrolled 1512 eligible participants in this prospective study. MASLD was defined by a controlled attenuation parameter (CAP) of ≥248 dB/m utilizing vibration-controlled transient elastography in conjunction with presence of ≥1 cardiometabolic risk factor. The distribution of MASLD and the changes in CAP were evaluated before treatment and at SVR12. Forward stepwise logistic regression analyses were performed to determine factors significantly associated with the regression or emergence of MASLD. RESULTS: The prevalence of MASLD decreased from 45.0% before treatment to 36.1% at SVR12. Among 681 participants with MASLD before treatment, 144 (21%) exhibited MASLD regression at SVR12. Conversely, among 831 participants without MASLD before treatment, 9 (1.1%) developed MASLD at SVR12. Absence of type 2 diabetes (T2D) [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.13-2.65, p = 0.011], age > 50 years (OR: 1.73, 95% CI: 1.11-2.68, p = 0.015), and alanine transaminase (ALT) ≤ 2 times the upper limit of normal (ULN) (OR: 1.56; 95% CI: 1.03-2.37, p = 0.035) were associated with the regression of MASLD. Presence of T2D was associated with the emergence of MASLD (OR: 5.83, 95% CI: 1.51-22.56, p = 0.011). CONCLUSIONS: The prevalence of MASLD decreased after achieving SVR12 with DAAs. Patients with pre-existing T2D showed a diminished probability of MASLD regression and a heightened risk of MASLD emergence post-SVR12.

The relationship between different fatty acids intake and the depressive symptoms: A population-based study.

BACKGROUND: Depression is a common psychological disorder worldwide, affecting mental and physical health. Previous studies have explored the benefits of polyunsaturated fatty acids (PUFAs) intake in depressive symptoms; however, few studies have focused on the association between all types of fatty acids intake and depressive symptoms. Therefore, we explored the relationship between the intake of different fatty acids intake and the risk of depressive symptoms. METHODS: The study was based on the data from the 2005-2018 National Health and Nutrition Examination Survey (NHANES), a large US-based database. We used a nutrient residual model and multi-nutrient density model for the analysis. We calculated the nutrient density and residual in men and women separately, and the fatty acids intake was divided into quartiles based on the sex distribution. The relationship between the depressive symptoms and the intake of different fatty acids was examined using logistic regression; furthermore, we explored the relationships separately in men and women. RESULTS: The intake of monounsaturated fatty acids (MUFAs) and PUFAs, particularly n-3 and n-6 PUFAs, were associated with reduced odds ratios for depressive symptoms. The inverse relationship between the intake of MUFAs, PUFAs, n-3, and n-6 PUFAs and depressive symptoms was stronger in women. The inverse relationship between total fatty acid (TFAs) intake and depressive symptoms existed only in a single model. In contrast, saturated fatty acid (SFAs) intake was not related to depressive symptoms. CONCLUSION: Consuming MUFAs and PUFAs can counteract the depressive symptoms, especially in women.

Kaempferol attenuates inflammation in lipopolysaccharide-induced gallbladder epithelial cells by inhibiting the MAPK/NF-κB signaling pathway.

Kaempferol (KPR), a flavonoid compound found in various plants and foods, has garnered attention for its anti-inflammatory, antioxidant, and anticancer properties. In preliminary studies, KPR can modulate several signaling pathways involved in inflammation, making it a candidate for treating cholecystitis. This study aimed to explore the effects and mechanisms of KPR on lipopolysaccharide (LPS)-induced human gallbladder epithelial cells (HGBECs). To assess the impact of KPR on HGBECs, the HGBECs were divided into control, KPR, LPS, LPS + KPR, and LPS + UDCA groups. Cell viability and cytotoxicity were evaluated by MTT assay and lactate dehydrogenase (LDH) assay, respectively, and concentrations of KPR (10-200 µM) were tested. LPS-induced inflammatory responses in HGBECs were to create an in vitro model of cholecystitis. The key inflammatory markers (IL-1ß, IL-6, and TNF-α) levels were quantified using ELISA, The modulation of the MAPK/NF-κB signaling pathway was measured by western blot using specific antibodies against pathway components (p-IκBα, IκBα, p-p65, p65, p-JNK, JNK, p-ERK, ERK, p-p38, and p38). The cell viability and LDH levels in HGBECs were not significantly affected by 50 µM KPR, thus it was selected as the optimal KPR intervention concentration. KPR increased the viability of LPS-induced HGBECs. Additionally, KPR inhibited the inflammatory factors level (IL-1ß, IL-6, and TNF-α) and protein expression (iNOS and COX-2) in LPS-induced HGBECs. Furthermore, KPR reversed LPS-induced elevation of p-IκBα/IκBα, p-p65/p65, p-JNK/JNK, p-ERK/ERK, and p-p38/p38 ratios. KPR attenuates the LPS-induced inflammatory response in HGBECs, possibly by inhibiting MAPK/NF-κB signaling.

Disparities in Mistreatment During Childbirth.

Importance: Lack of respectful maternity care may be a key factor associated with disparities in maternal health. However, mistreatment during childbirth has not been widely documented in the US. Objectives: To estimate the prevalence of mistreatment by health care professionals during childbirth among a representative multistate sample and to identify patient characteristics associated with mistreatment experiences. Design, Setting, and Participants: This cross-sectional study used representative survey data collected from respondents to the 2020 Pregnancy Risk and Monitoring System in 6 states and New York City who had a live birth in 2020 and participated in the Postpartum Assessment of Health Survey at 12 to 14 months' post partum. Data were collected from January 1, 2021, to March 31, 2022. Exposures: Demographic, social, clinical, and birth characteristics that have been associated with patients' health care experiences. Main Outcomes and Measures: Any mistreatment during childbirth, as measured by the Mistreatment by Care Providers in Childbirth scale, a validated measure of self-reported experiences of 8 types of mistreatment. Survey-weighted rates of any mistreatment and each mistreatment indicator were estimated, and survey-weighted logistic regression models estimated odds ratios (ORs) and 95% CIs. Results: The sample included 4458 postpartum individuals representative of 552 045 people who had live births in 2020 in 7 jurisdictions. The mean (SD) age was 29.9 (5.7) years, 2556 (54.4%) identified as White, and 2836 (58.8%) were commercially insured. More than 1 in 8 individuals (13.4% [95% CI, 11.8%-15.1%]) reported experiencing mistreatment during childbirth. The most common type of mistreatment was being "ignored, refused request for help, or failed to respond in a timely manner" (7.6%; 95% CI, 6.5%-8.9%). Factors associated with experiencing mistreatment included being lesbian, gay, bisexual, transgender, queer identifying (unadjusted OR [UOR], 2.3; 95% CI, 1.4-3.8), Medicaid insured (UOR, 1.4; 95% CI, 1.1-1.8), unmarried (UOR, 0.8; 95% CI, 0.6-1.0), or obese before pregnancy (UOR, 1.3; 95% CI, 1.0-1.7); having an unplanned cesarean birth (UOR, 1.6; 95% CI, 1.2-2.2), a history of substance use disorder (UOR, 2.6; 95% CI, 1.3-5.1), experienced intimate partner or family violence (UOR, 2.3; 95% CI, 1.3-4.2), mood disorder (UOR, 1.5; 95% CI, 1.1-2.2), or giving birth during the COVID-19 public health emergency (UOR, 1.5; 95% CI, 1.1-2.0). Associations of mistreatment with race and ethnicity, age, educational level, rural or urban geography, immigration status, and household income were ambiguous. Conclusions and Relevance: This cross-sectional study of individuals who had a live birth in 2020 in 6 states and New York City found that mistreatment during childbirth was common. There is a need for patient-centered, multifaceted interventions to address structural health system factors associated with negative childbirth experiences.

A Combined Measure of the Triglyceride Glucose Index and Trimethylamine N-Oxide in Risk Stratification of ST-Segment Elevation Myocardial Infarction Patients with High-Risk Plaque Features Defined by Optical Coherence Tomography: A Substudy of the OCTAMI Registry Study.

Background and Aim: An elevated triglyceride-glucose (TyG) level is associated with increased risk of mortality in patients with CAD. Trimethylamine N-oxide (TMAO) has mechanistic links to atherosclerotic coronary artery disease (CAD) pathogenesis and is correlated with adverse outcomes. However, the incremental prognostic value of TMAO and TyG in the cohort of optical coherence tomography (OCT)-defined high-risk ST-segment elevation myocardial infarction (STEMI) patients is unknown. Methods: We studied 274 consecutive aged ≥18 years patients with evidence of STEMI and detected on pre-intervention OCT imaging of culprit lesions between March 2017 and March 2019. Outcomes: There were 22 (22.68%), 27 (27.84%), 26 (26.80%), and 22 (22.68%) patients in groups A-D, respectively. The baseline characteristics according to the level of TMAO and TyG showed that patients with higher level in both indicators were more likely to have higher triglycerides (p < 0.001), fasting glucose (p < 0.001) and higher incidence of diabetes (p = 0.008). The group with TMAO > median and TyG ≤ median was associated with higher rates of MACEs significantly (p = 0.009) in fully adjusted analyses. During a median follow-up of 2.027 years, 20 (20.6%) patients experienced MACEs. To evaluate the diagnostic value of the TyG index combined with TMAO, the area under the receiver operating characteristic curve for predicting MACEs after full adjustment was 0.815 (95% confidence interval, 0.723-0.887; sensitivity, 85.00%; specificity, 72.73%; cut-off level, 0.577). Among the group of patients with TMAO > median and TyG ≤ median, there was a significantly higher incidence of MACEs (p=0.033). A similar tendency was found in the cohort with hyperlipidemia (p=0.016) and diabetes mellitus (p=0.036). Conclusion: This study demonstrated the usefulness of combined measures of the TyG index and TMAO in enhancing risk stratification in STEMI patients with OCT-defined high-risk plaque characteristics. Trial Registration: This study was registered at ClinicalTrials.gov as NCT03593928.

Bee chitosan nanoparticles loaded with apitoxin as a novel approach to eradication of common human bacterial, fungal pathogens and treating cancer.

Antimicrobial resistance is one of the largest medical challenges because of the rising frequency of opportunistic human microbial infections across the globe. This study aimed to extract chitosan from the exoskeletons of dead bees and load it with bee venom (commercially available as Apitoxin [Api]). Then, the ionotropic gelation method would be used to form nanoparticles that could be a novel drug-delivery system that might eradicate eight common human pathogens (i.e., two fungal and six bacteria strains). It might also be used to treat the human colon cancer cell line (Caco2 ATCC ATP-37) and human liver cancer cell line (HepG2ATCC HB-8065) cancer cell lines. The x-ray diffraction (XRD), Fourier transform infrared (FTIR), and dynamic light scattering (DLS) properties, ζ-potentials, and surface appearances of the nanoparticles were evaluated by transmission electron microscopy (TEM). FTIR and XRD validated that the Api was successfully encapsulated in the chitosan nanoparticles (ChB NPs). According to the TEM, the ChB NPs and the ChB NPs loaded with Apitoxin (Api@ChB NPs) had a spherical shape and uniform size distribution, with non-aggregation, for an average size of approximately 182 and 274 ± 3.8 nm, respectively, and their Zeta potential values were 37.8 ± 1.2 mV and - 10.9 mV, respectively. The Api@ChB NPs had the greatest inhibitory effect against all tested strains compared with the ChB NPs and Api alone. The minimum inhibitory concentrations (MICs) of the Api, ChB NPs, and Api@ChB NPs were evaluated against the offer mentioned colony forming units (CFU/mL), and their lowest MIC values were 30, 25, and 12.5 µg mL-1, respectively, against Enterococcus faecalis. Identifiable morphological features of apoptosis were observed by 3 T3 Phototox software after Api@ChB NPs had been used to treat the normal Vero ATCC CCL-81, Caco2 ATCC ATP-37, and HepG2 ATCC HB-8065 cancer cell lines for 24 h. The morphological changes were clear in a concentration-dependent manner, and the ability of the cells was 250 to 500 µg mL-1. These results revealed that Api@ChB NPs may be a promising natural nanotreatment for common human pathogens.

Association between white matter hyperintensity and anxiety/depression.

Although previous studies have explored the associations of white matter hyperintensity with psychiatric disorders, the sample size is small and the conclusions are inconsistent. The present study aimed to further systematically explore the association in a larger sample. All data were extracted from the UK Biobank. First, general linear regression models and logistic regression models were used to assess the association between white matter hyperintensity volume and anxiety/depression. White matter hyperintensity has been classified into periventricular white matter hyperintensity and deep white matter hyperintensity. Anxiety was determined by General Anxiety Disorder-7 score (n = 17,221) and self-reported anxiety (n = 15,333), depression was determined by Patient Health Questionnaire-9 score (n = 17,175), and self-reported depression (n = 14,519). Moreover, we employed Cox proportional hazard models to explore the association between white matter hyperintensity volume and anxiety/depression. The covariates included in fully adjusted model are age, gender, body mass index, Townsend deprivation index, healthy physical activity, cigarette consumption, alcohol consumption, educational attainment, diabetes, hypertension, and coronary heart disease. The results of the fully adjusted model showed that white matter hyperintensity volume was significantly associated with General Anxiety Disorder-7 score (periventricular white matter hyperintensity: ß = 0.152, deep white matter hyperintensity: ß = 0.094) and Patient Health Questionnaire-9 score (periventricular white matter hyperintensity: ß = 0.168). Logistic regression analysis results indicated that periventricular white matter hyperintensity volume (odds ratio = 1.153) was significantly associated with self-reported anxiety. After applying the Cox proportional hazard models, we found that larger white matter hyperintensity volume was associated with increased risk of depression (periventricular white matter hyperintensity: hazard ratio = 1.589, deep white matter hyperintensity: hazard ratio = 1.200), but not anxiety. In summary, our findings support a positive association between white matter hyperintensity volume and depression.

The evolution of robotics: research and application progress of dental implant robotic systems.

The use of robots to augment human capabilities and assist in work has long been an aspiration. Robotics has been developing since the 1960s when the first industrial robot was introduced. As technology has advanced, robotic-assisted surgery has shown numerous advantages, including more precision, efficiency, minimal invasiveness, and safety than is possible with conventional techniques, which are research hotspots and cutting-edge trends. This article reviewed the history of medical robot development and seminal research papers about current research progress. Taking the autonomous dental implant robotic system as an example, the advantages and prospects of medical robotic systems would be discussed which would provide a reference for future research.

Demonstration of 10 nm Ferroelectric Al0.7Sc0.3N-Based Capacitors for Enabling Selector-Free Memory Array.

In this work, 10 nm scandium-doped aluminum nitride (AlScN) capacitors are demonstrated for the construction of the selector-free memory array application. The 10 nm Al0.7Sc0.3N film deposited on an 8-inch silicon wafer with sputtering technology exhibits a large remnant polarization exceeding 100 µC/cm2 and a tight distribution of the coercive field, which is characterized by the positive-up-negative-down (PUND) method. As a result, the devices with lateral dimension of only 1.5 µm show a large memory window of over 250% and a low power consumption of ~40 pJ while maintaining a low disturbance rate of <2%. Additionally, the devices demonstrate stable multistate memory characteristics with a dedicated operation scheme. The back-end-of-line (BEOL)-compatible fabrication process, along with all these device performances, shows the potential of AlScN-based capacitors for the implementation of the high-density selector-free memory array.

Transcriptome analysis of Kluyveromyces marxianus under succinic acid stress and development of robust strains.

Kluyveromyces marxianus has become an attractive non-conventional yeast cell factory due to its advantageous properties such as high thermal tolerance and rapid growth. Succinic acid (SA) is an important platform molecule that has been applied in various industries such as food, material, cosmetics, and pharmaceuticals. SA bioproduction may be compromised by its toxicity. Besides, metabolite-responsive promoters are known to be important for dynamic control of gene transcription. Therefore, studies on global gene transcription under various SA concentrations are of great importance. Here, comparative transcriptome changes of K. marxianus exposed to various concentrations of SA were analyzed. Enrichment and analysis of gene clusters revealed repression of the tricarboxylic acid cycle and glyoxylate cycle, also activation of the glycolysis pathway and genes related to ergosterol synthesis. Based on the analyses, potential SA-responsive promoters were investigated, among which the promoter strength of IMTCP2 and KLMA_50231 increased 43.4% and 154.7% in response to 15 g/L SA. In addition, overexpression of the transcription factors Gcr1, Upc2, and Ndt80 significantly increased growth under SA stress. Our results benefit understanding SA toxicity mechanisms and the development of robust yeast for organic acid production. KEY POINTS: • Global gene transcription of K. marxianus is changed by succinic acid (SA) • Promoter activities of IMTCP2 and KLMA_50123 are regulated by SA • Overexpression of Gcr1, Upc2, and Ndt80 enhanced SA tolerance.

A Preclinical Blinded Randomized-Controlled Trial Evaluating the Clinical Relevance of Polyp Size Measurement Using a Virtual Scale Endoscope.

Background: The virtual scale endoscope (VSE) helps endoscopists measure colorectal polyp size more accurately compared to visual assessment (VA). However, previous studies were not adequately powered to evaluate the sizing of polyps at clinically relevant size thresholds and relative accuracy for size subgroups. Methods: We created 64 artificial polyps of varied sizes and Paris class morphology, randomly assigned 1:1 to be measured (383 total measurement datapoints with VSE and VA by 6 endoscopists blinded to true size) in a colon model. We added data from two previous trials (480 measurement datapoints). We evaluated for correct classification of polyps into size groups at 3 mm, 5 mm, 10 mm, and 20 mm size thresholds and the relative size measurement accuracy for diminutive polyps (≤5 mm), small polyps (5-9 mm), large polyps at 10-19 mm, and polyps (≥20). Results: VSE had significantly less size group misclassifications at the 5 mm, and 10 mm thresholds (28 percent vs. 45 percent, P = 0.0159 and 26 percent vs. 44 percent, P = 0.0135, respectively). For the 3 mm and 20 mm thresholds, VSE had lower misclassifications; however, this was not statistically significant (36 percent vs. 46 percent, P = 0.3853 and 38 percent vs. 41 percent, P = 0.2705, respectively). The relative size measurement accuracy was significantly higher for VSE compared to VA for all size subgroups (diminutive (P < 0.01), small polyps (P < 0.01), 10-19 mm (P < 0.01), and ≥20 mm (P < 0.01)). Conclusion: VSE outperforms VA in categorizing polyps into size groups at the clinically relevant size thresholds of 5 mm and 10 mm. Using VSE resulted in significantly higher relative measurement accuracy for all size subgroups.

Burden of Stroke Attributable to Nonoptimal Temperature in 204 Countries and Territories: A Population-Based Study, 1990-2019.

BACKGROUND AND OBJECTIVES: Stroke attributable to nonoptimal temperature needs more attention with dramatic climate change. The aim of this study was to estimate the global burden and distribution characteristics of the burden. METHODS: In this ecological study, we collected data from the Climate Research Unit Gridded Time Series, the World Bank databases, and the Global Burden of Diseases study to estimate the distribution of burden. We used the joinpoint model, decomposition analysis, age-period-cohort model, panel data analysis, and health inequality analysis to assess the different types of stroke burden attributable to different climatic conditions. RESULTS: The burden of stroke attributable to nonoptimal temperature continued to grow, and aging was a key factor in this increase. In 2019, 521,031 (95% uncertainty interval [UI] 402,433-663,996) deaths and 9,423,649 (95% UI 7,207,660-12,055,172) disability-adjusted life years [DALYs] attributable to stroke due to nonoptimal temperature were recorded globally. Globally, men (age-standardized mortality rate [ASMR] 7.70, 95% UI 5.80-9.73; age-standardized DALY rate [ASDR] 139.69, 95% UI 102.96-178.54 in 2019) had a heavier burden than women (ASMR 5.89, 95% UI 4.50-7.60; ASDR 96.02, 95% UI 72.62-123.85 in 2019). Central Asia (ASMR 18.12, 95% UI 13.40-24.53; ASDR 327.35, 95% UI 240.24-440.61 in 2019) had the heaviest burden at the regional level. In the national level, North Macedonia (ASMR 32.97, 95% UI 20.57-47.44 in 2019) and Mongolia (ASDR 568.54, 95% UI 242.03-1,031.14 in 2019) had the highest ASMR/ASDR, respectively. Low temperature currently contributes to the main burden (deaths 474,002, 95% UI 355,077-606,537; DALYs 8,357,198, 95% UI 6,186,217-10,801,911 attributable to low temperature vs deaths 48,030, 95% UI 5,630-104,370; DALYs 1,089,329, 95% UI 112,690-2,375,345 attributable to high temperature in 2019). However, the burden due to high temperature has increased rapidly, especially among people aged older than 10 years, and was disproportionately concentrated in low sociodemographic index (SDI) regions such as Africa. In addition, the rapid increase in the stroke burden due to high temperature in Central Asia also requires special attention. DISCUSSION: This is the first study to assess the global stroke burden attributed to nonoptimal temperature. The dramatic increase in the burden due to high temperature requires special attention, especially in low-SDI countries.

Synthesis and biological evaluation of 4-imidazolidinone-containing compounds as potent inhibitors of the MDM2/p53 interaction.

Inhibition of MDM2/p53 interaction with small-molecule inhibitors stabilizes p53 from MDM2 mediated degradation, which is a promising strategy for the treatment of cancer. In this report, a novel series of 4-imidazolidinone-containing compounds have been synthesized and tested in MDM2/p53 and MDM4/p53 FP binding assays. Upon SAR studies, compounds 2 (TB114) and 22 were identified as the most potent inhibitors of MDM2/p53 but not MDM4/p53 interactions. Both 2 and 22 exhibited strong antiproliferative activities in HCT-116 and MOLM-13 cell lines harboring wild type p53. Mechanistic studies show that 2 and 22 dose-dependently activated p53 and its target genes and induced apoptosis in cells based on the Western blot, qPCR, and flow cytometry assays. In addition, the antiproliferative activities of 2 and 22 were dependent on wild type p53, while they were not toxic to HEK-293 kidney cells. Furthermore, the on-target activities of 2 were general and applicable to other cancer cell lines with wild type p53. These attributes make 2 a good candidate for future optimization to discover a potential treatment of wild-type p53 cancer.

Jolkinolide B synergistically potentiates the antitumor activity of GPX4 inhibitors via inhibiting TrxR1 in cisplatin-resistant bladder cancer cells.

Glutathione peroxidase 4 (GPX4) is a promising anticancer therapeutic target; however, the application of GPX4 inhibitors (GPX4i) is limited owing to intrinsic or acquired drug resistance. Hence, understanding the mechanisms underlying drug resistance and discovering molecules that can overcome drug resistance are crucial. Herein, we demonstrated that GPX4i killed bladder cancer cells by inducing lipid reactive oxygen species-mediated ferroptosis and apoptosis, and cisplatin-resistant bladder cancer cells were also resistant to GPX4i, representing a higher half-maximal inhibitory concentration value than that of parent bladder cancer cells. In addition, thioredoxin reductase 1 (TrxR1) overexpression was responsible for GPX4i resistance in cisplatin-resistant bladder cancer cells, and inhibiting TrxR1 restored the sensitivity of these cells to GPX4i. In vitro and in vivo studies revealed that Jolkinolide B (JB), a natural diterpenoid and previously identified as a TrxR1 inhibitor, potentiated the antiproliferative efficacy of GPX4i (RSL3 and ML162) against cisplatin-resistant bladder cancer cells. Furthermore, GPX4 knockdown and inhibition could augment JB-induced paraptosis and apoptosis. Our results suggest that inhibiting TrxR1 can effectively improve GPX4 inhibition-based anticancer therapy. A combination of JB and GPX4i, which is well-tolerated and has several anticancer mechanisms, may serve as a promising therapy for treating bladder cancer.

Selenite selectively kills lung fibroblasts to treat bleomycin-induced pulmonary fibrosis.

BACKGROUND: Interstitial lung disease (ILD) treatment is a critical unmet need. Selenium is an essential trace element for human life and an antioxidant that activates glutathione, but the gap between its necessity and its toxicity is small and requires special attention. Whether selenium can be used in the treatment of ILD remains unclear. METHODS: We investigated the prophylactic and therapeutic effects of selenite, a selenium derivative, in ILD using a murine model of bleomycin-induced idiopathic pulmonary fibrosis (IPF). We further elucidated the underlying mechanism using in vitro cell models and examined their relevance in human tissue specimens. The therapeutic effect of selenite in bleomycin-administered mice was assessed by respiratory function and histochemical changes. Selenite-induced apoptosis and reactive oxygen species (ROS) production in murine lung fibroblasts were measured. RESULTS: Selenite, administered 1 day (inflammation phase) or 8 days (fibrotic phase) after bleomycin, prevented and treated deterioration of lung function and pulmonary fibrosis in mice. Mechanistically, selenite inhibited the proliferation and induced apoptosis of murine lung fibroblasts after bleomycin treatment both in vitro and in vivo. In addition, selenite upregulated glutathione reductase (GR) and thioredoxin reductase (TrxR) in murine lung fibroblasts, but not in lung epithelial cells, upon bleomycin treatment. GR and TrxR inhibition eliminates the therapeutic effects of selenite. Furthermore, we found that GR and TrxR were upregulated in the human lung fibroblasts of IPF patient samples. CONCLUSIONS: Selenite induces ROS production and apoptosis in murine lung fibroblasts through GR and TrxR upregulation, thereby providing a therapeutic effect in bleomycin-induced IPF.

KLRB1 defines an activated phenotype of CD4+ T cells and shows significant upregulation in patients with primary Sjögren's syndrome.

OBJECTIVE: This study aimed to investigate the role of KLRB1 (CD161) in human CD4+ T cells and elucidate its significance in primary Sjögren's syndrome (pSS). METHODS: Peripheral blood samples from 37 healthy controls and 44 pSS patients were collected. The publicly available single-cell RNA-Seq data from pSS patient PBMCs were utilized to analyse KLRB1 expression in T cells. KLRB1-expressing T lymphocyte subset proportions in pSS patients and healthy controls were determined by flow cytometry. CD25, Ki-67, cytokine secretion, and chemokine receptor expression in CD4+ KLRB1+ T cells were detected and compared with those in CD4+ KLRB1- T cells. Correlation analysis was conducted between KLRB1-related T-cell subsets and clinical indicators. ROC curves were generated to explore the diagnostic potential of KLRB1 for pSS. RESULTS: KLRB1 was significantly upregulated following T-cell activation, and Ki-67 and CD25 expression was significantly greater in CD4+ KLRB1+ T cells than in CD4+ KLRB1- T cells. KLRB1+ CD4+ T cells exhibited greater IL-17A, IL-21, IL-22, and IFN-γ secretion upon stimulation, and there were significantly greater proportions of CCR5+, CCR2+, CX3CR1+, CCR6+, and CXCR3+ cells among CD4+ KLRB1+ T cells than among CD4+ KLRB1- T cells. Compared with that in HCs, KLRB1 expression in CD4+ T cells was markedly elevated in pSS patients and significantly correlated with clinical disease indicators. CONCLUSION: KLRB1 is a characteristic molecule of the CD4+ T-cell activation phenotype. The increased expression of KLRB1 in the CD4+ T cells of pSS patients suggests its potential involvement in the pathogenesis of pSS and its utility as an auxiliary diagnostic marker for pSS.

Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy.

Backgrounds and Aim: Chronic hepatitis C (CHC) patients who fail antiviral therapy have a high risk of developing hepatocellular carcinoma (HCC). We investigated the effects of metformin and statins, commonly used to treat diabetes mellitus (DM) and hyperlipidemia (HLP), on HCC risk in CHC patients who failed antiviral therapy. Methods: CHC patients with failed interferon-based therapy were enrolled in a large-scale multicenter cohort study in Taiwan (T-COACH). HCC occurrence 1.5 years after the end of antiviral therapy was identified by linking to the cancer registry databases from 2003 to 2019. After considering death and liver transplantation as competing risks, Gray's cumulative incidence and Cox sub-distribution hazards for HCC development were used. Results: Among the 2,779 CHC patients, 480 (17.3%) developed new-onset HCC and 238 (8.6%) died after antiviral therapy. Metformin non-users with DM had a 51% higher risk of liver cancer than patients without DM, while statin users with HLP had a 50% lower risk of liver cancer than patients without HLP. The 5-year cumulative incidence of HCC was 16.5% in metformin non-users, significantly higher in metformin non-users than in patients without DM (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Conversely, HLP statin users had a significantly lower HCC risk than patients without HLP (3.8% vs. 12.5%; aSHR=0.50; P<0.001). Notably, the unfavorable effect of non-metformin use on increased HCC risk was mainly observed among patients without cirrhosis but not in patients with cirrhosis. In contrast, a favorable effect of statins reduced the risk of HCC in both cirrhotic and non-cirrhotic patients. Conclusion: Metformin for DM and statins for HLP have chemopreventive effects on HCC risk in CHC patients who failed antiviral therapy. These findings emphasize the importance of personalized preventive strategies for managing patients with these clinical profiles.