Clinicopathological features, prognostic factors, and prognostic survival prediction in patients with extrahepatic bile duct cancer liver metastasis.

PURPOSE: Extrahepatic bile duct cancer (EBDC) is a compound malignant tumor mainly consisting of extrahepatic cholangiocarcinoma and gallbladder carcinoma. Most EBDC patients are diagnosed at an advanced stage characterized by distant metastases, and the liver is one of the common sites of metastasis. Hence, the purpose of this study is to investigate the clinicopathological features, identify prognostic risk factors, and assess the long-term prognosis of extrahepatic bile duct cancer liver metastasis (EBDCLM). METHODS: We identified 1922 eligible EBDCLM patients from the SEER database.Cox regression models were used to predict independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS),and Kaplan-Meier survival curves were drawn. A nomogram was constructed based on the results of multivariate Cox analysis, and the predictive effect of the nomogram was evaluated. RESULTS: Age, surgery, chemotherapy, brain metastasis, and lung metastasis were common independent prognostic factors for OS and CSS, and radiotherapy and bone metastasis were independent prognostic factors for CSS. The Kaplan-Meier survival curves showed a significant increase in survival for patients aged less than or equal to 70 years, undergoing surgery and chemotherapy, and without lung metastases. The results showed that the nomogram constructed by us had good predictability and ha d strong clinical application value. CONCLUSION: Our study identified age, surgery, chemotherapy, brain metastasis, and lung metastasis as independent prognostic factors for EBDCLM patients. The nomogram can accurately predict the survival probability, which is helpful for clinicians to assess the prognosis of patients with advanced EBDC and provide personalized clinical decisions.

Joinpoint regression analysis of recent trends in desmoplastic malignant melanoma incidence and mortality: 15-year multicentre retrospective study.

BACKGROUND: Recent data reveal a marked rise in the detection and mortality rates of Desmoplastic Malignant Melanoma (DMM). This trend underscores the imperative for an in-depth analysis of DMM's epidemiology, which is crucial for the formulation of precise medical and public health strategies. This investigation seeks to elucidate the variations in the incidence and mortality of DMM over a 15-year period (2005-2019). METHODS: Data on DMM patients was sourced from the Surveillance, Epidemiology, and End Results (SEER) database. Both incidence and incidence-based mortality rates (IBM) were directly extracted from the SEER database. Joinpoint regression was used to analyze and calculate the average annual percent change (AAPC) and its 95% confidence interval (CI). RESULTS: Between 2005 and 2019, 3,384 DMM cases were identified, boasting an age-adjusted incidence rate of 36.3 cases per 1000,000 person-years (95% CI 3.51-3.76) and an IBM of 1.65cases per 1000,000 person-years (95% CI 1.57-1.74). Of these, 2,353 were males (69.53%) and 1,031 were females (30.47%). There were 1894 patients (55.97%) who were over 70 years old. Predominantly, DMM lesions manifested in exposed areas: Limbs (955, 28.22%), Face (906, 26.77%), and Scalp and Neck (865, 25.56%). The incidence of DMM increased significantly at a rate of APC = 0.9% during 2005-2019, while the incidence-based mortality showed a significant upward trend (APC = 7%) during 2005-2012, and slowly increasing trend (APC = 0.6%) during 2012-2019. In contrast to the modest upward trajectory in female incidence and mortality, male incidence initially surged, later declining, while male mortality peaked and stabilized post-2012. The primary sites for incidence and mortality were chronically sun-exposed areas: Face, Scalp and Neck, and Limbs. CONCLUSIONS: In recent years, the incidence and incidence-based mortality of DMM have significantly increased. Each subgroup analysis has different trends, and these trends can provide better support for our exploration of DMM.

Comparative chemical profiling of leaf essential oils from Cinnamomum kanehirae and related species using steam distillation and solvent extraction: Implications for plant-based classification.

Cinnamomum kanehirae Hayata, belonging to Lauraceae family, is an indigenous and endangered species of considerable economic importance in Taiwan. It plays a crucial role as the host for the economically valuable saprotrophic fungus, Taiwanofungus camphorates. However, accurate species identification poses a challenge due to the similarity in morphological features and frequent natural hybridization with closely related species. Acquiring high-quality and pure leaf oils becomes imperative for precise species identification and producing superior goods. In this study, our objective was to establish methodologies for analyzing the chemical composition of leaf essential oils and subsequently apply this knowledge to differentiate among three Cinnamomum species. Gas chromatography-mass spectrometry (GC/MS) was employed to scrutinize the chemical makeup of leaf essential oils from three closely related species: C. kanehirae, C. micranthum, and C. camphora. We utilized Steam Distillation (SD) and steam distillation-solvent extraction (SDSE) methods, with the SDSE-Hexane approach chosen for optimization, enhancing extraction efficiency and ensuring essential oil purity. Through the SDSE-Hexane method, we identified seventy-four compounds distributed across three major classes: monoterpenes hydrocarbons (0.0-7.0 %), oxygenated monoterpenes (3.8-90.9 %), sesquiterpenes hydrocarbons (0.0-28.3 %), and oxygenated sesquiterpenes (1.6-88.1 %). Our findings indicated the presence of more than one chemotype in both C. kanehirae and C. camphora, whereas no specific chemotype could be discerned in C. micranthum. Furthermore, clustering based on chemotypes allowed for the differentiation of samples from the three species. Notably, we demonstrated that the chemical compositions of grafted C. kanehirae remained largely unaffected by the rootstock. Conversely, natural hybrids between C. kanehirae and C. camphora exhibited profiles more closely aligned with C. kanehirae. The optimized extraction method and the chemotype-based classification system established in this study present valuable tools for essential oil preparation, species identification, and further exploration into the genetic variation of Cinnamomum.

Three species of rape responded to cadmium and melatonin alleviating Cd-toxicity in species-specific strategy.

Cadmium (Cd) pollution has been a significant concern in heavy metal pollution, prompting plants to adopt various strategies to mitigate its damage. While the response of plants to Cd stress and the impact of exogenous melatonin has received considerable attention, there has been limited focus on the responses of closely related species to these factors. Consequently, our investigation aimed to explore the response of three different species of rape to Cd stress and examine the influence of exogenous melatonin in this scenario. The research findings revealed distinctive responses among the investigated rape species. B. campestris showed the resistance to Cd and exhibited lower Cd absorption and sustained its physiological activity under Cd stress. In contrast, B. juncea accumulated much Cd and increased the amount of anthocyanin to mitigate the Cd-damage. Furthermore, B. napus showed the tolerance to Cd and tended to accumulate Cd in vacuoles under Cd stress, thereby decreasing the Cd damage and leading to higher activity of antioxidant enzymes and photosynthesis. Moreover, the application of exogenous melatonin significantly elevated the melatonin level in plants and mitigated Cd toxicity by promoting the activity of antioxidant enzymes, reducing Cd absorption, enhancing the chelating capacity with Cd, decreasing Cd accumulation in organelles, and reducing its fluidity. Specifically, exogenous melatonin increased the FHAc content in B. campestris, elevated the phytochelatins (PCs) level in B. napus, and stimulated photosynthesis in B. juncea. In summary, the findings underscore the species-specific responses of the three species of rape to both Cd stress and exogenous melatonin, highlighting the potential for tailored mitigation strategies based on the unique characteristics of each species.

Zhuang-Gu-Fang promotes osteoblast differentiation via myoblasts and myoblast-derived exosomal miRNAs:miR-5100, miR-126a-3p, miR-450b-5p, and miR-669a-5p.

BACKGROUND: Senile osteoporosis (SOP) is an age-related systemic metabolic bone disorder. Previous studies have proved that Zhuang-Gu-Fang (ZGF) modulates myokines, stimulates osteogenic differentiation, and mitigates osteoporosis. OBJECTIVE: To elucidate the mechanism by which ZGF promotes osteogenic differentiation via myoblast and myoblast exosomal microRNAs (miRNAs) and investigate its potential implications in senile osteoporosis. METHODS: Characterization of ZGF and ZGF serum using UHPLC-MS/MS. An alkaline phosphatase (ALP) activity assay and staining techniques were employed to corroborate the impacts of ZGF on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) via myoblasts. Subsequently, exosomes derived from myoblasts were isolated through ultracentrifugation. The effects of ZGF on the BMSCs' osteogenic differentiation were substantiated through ALP activity, alizarin red staining, and a quantitative real-time polymerase reaction system (qRT-PCR). Selected miRNAs were identified via high-throughput sequencing and subjected to differential expression analysis, and subsequently validated through qRT-PCR. The senescence-accelerated (SAMP6) mice were selected as the SOP models. qRT-PCR analyses were further conducted to confirm the expression levels of these selected miRNAs in the muscle and bone tissues of the SAMP6 mice, and the protein expression of osteogenesis-related transcription factors OCN and Osterix in its bone tissue was evaluated by immunofluorescence staining analysis (IF). RESULTS: ZGF may enhance the osteogenic differentiation of BMSCs through myoblasts and myoblast-derived exosomes. High-throughput sequencing, differential expression analysis, and subsequent qRT-PCR validation identified four miRNAs that stood out due to their significant differential expression: miR-5100, miR-142a-3p, miR-126a-3p, miR-450b-5p and miR-669a-5p. Moreover, the mice experiment corroborated these findings, which revealed that ZGF not only up-regulated the expression of miR-5100, miR-450b-5p and miR-126a-3p in muscle and bone tissues but also concurrently down-regulated the expression of miR-669a-5p in these tissues. IF staining analysis indicated that ZGF can significantly increase the protein expression of the osteogenic transcription factors OCN and Osterix in the bone tissue of mice with SOP. CONCLUSIONS: ZGF can promote osteogenic differentiation of osteoblasts, regulate bone metabolism, and thereby delay the process of SOP. Perhaps, its mechanism is to upregulate myoblast-derived exosomes miR-5100, miR-126a-3p, and miR-450b-5p or downregulate miR-669a-5p. This study reports for the first time that myoblast exosomes miR-669a-5p and miR-450b-5p are novel targets for the regulation of osteoblastic differentiation and the treatment of SOP.

Radiomic signatures associated with tumor immune heterogeneity predict survival in locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The prognostic value of traditional clinical indicators for locally recurrent nasopharyngeal carcinoma (lrNPC) is limited due to their inability to reflect intratumor heterogeneity. We aimed to develop a radiomic signature to reveal tumor immune heterogeneity and predict survival in lrNPC. METHODS: This multicenter, retrospective study included 921 patients with lrNPC. A machine learning signature and nomogram based on pretreatment MRI features were developed for predicting overall survival (OS) in a training cohort and validated in two independent cohorts. A clinical nomogram and an integrated nomogram were constructed for comparison. Nomogram performance was evaluated by concordance index (C-index) and receiver operating characteristic curve analysis. Accordingly, patients were classified into risk groups. The biological characteristics and immune infiltration of the signature were explored by RNA sequencing (RNA-seq) analysis. RESULTS: The machine learning signature and nomogram demonstrated comparable prognostic ability to a clinical nomogram, achieving C-indexes of 0.729, 0.718, and 0.731 in the training, internal, and external validation cohorts, respectively. Integration of the signature and clinical variables significantly improved the predictive performance. The proposed signature effectively distinguished patients between risk groups with significantly distinct OS rates. Subgroup analysis indicated the recommendation of local salvage treatments for low-risk patients. Exploratory RNA-seq analysis revealed differences in interferon response and lymphocyte infiltration between risk groups. CONCLUSIONS: An MRI-based radiomic signature predicted OS more accurately. The proposed signature associated with tumor immune heterogeneity may serve as a valuable tool to facilitate prognostic stratification and guide individualized management for lrNPC patients.

Study on the Antitumor Mechanism of Tanshinone IIA In Vivo and In Vitro through the Regulation of PERK-ATF4-HSPA5 Pathway-Mediated Ferroptosis.

As a traditional Chinese medicine, Salvia miltiorrhiza Bunge was first recorded in the Shennong Materia Medica Classic and is widely used to treat "the accumulation of symptoms and masses". The main active ingredient of Salvia miltiorrhiza Bunge, Tanshinone IIA (TIIA), has shown anti-inflammatory, antitumor, antifibrosis, antibacterial, and antioxidative activities, etc. In this study, the results showed that TIIA could inhibit the proliferation and migration of HepG2 cells and downregulate glutathione (GSH) and Glutathione Peroxidase 4 (GPX4) levels; besides, TIIA induced the production of Reactive Oxygen Species (ROS), and upregulated the total iron content. Based on network pharmacology analysis, the antitumor effect of TIIA was found to be focused on the endoplasmic reticulum (ER)-mediated ferroptosis signaling pathway, with protein kinase R (PKR)-like ER kinase (PERK)-activating transcription factor 4 (ATF4)-heat shock 70 kDa protein 5 (HSPA5) as the main pathway. Herein, TIIA showed typical ferroptosis characteristics, and a ferroptosis inhibitor (ferrostatin-1) was used to verify the effect. The antitumor effects of TIIA, occurring through the inhibition of the PERK-ATF4-HSPA5 pathway, were further observed in vivo as significantly inhibited tumor growth and the improved pathological morphology of tumor tissue in H22-bearing mice. In summary, the antitumor mechanism of TIIA might be related to the downregulation of the activation of PERK-ATF4-HSPA5 pathway-mediated ferroptosis.

Endogenous H2S-activated Ag nanoparticles embedded in programmed DNA-cubes for specific visualization of colorectal cancer cells.

To avoid the unexpected aggregation and reduce the cytotoxicity of nanomaterials as optical probes in cell imaging applications, we propose a programmed DNA-cube as a carrier for silver nanoparticles (Ag NPs) to construct a specific hydrogen sulfide (H2S) responsive platform (Ag NP@DNA-cube) for diagnosing colorectal cancer (CRC) in this study. The DNA-cube maintains good dispersion of Ag NPs while providing excellent biocompatibility. Based on the characteristic overexpression of endogenous H2S in CRC cells, the Ag NPs are etched by H2S within target cells into silver sulfide quantum dots, thereby selectively illuminating the target cells. The Ag NP@DNA-cube exhibits a specific fluorescence response to CRC cells and achieves satisfactory imaging.

Knotted Artificial Muscles for Bio-Mimetic Actuation under Deepwater.

Muscles featuring high frequency and high stroke linear actuation are essential for animals to achieve superior maneuverability, agility, and environmental adaptability. Artificial muscles are yet to match their biological counterparts, due to inferior actuation speed, magnitude, mode, or adaptability. Inspired by the hierarchical structure of natural muscles, artificial muscles are created that are powerful, responsive, robust, and adaptable. The artificial muscles consist of knots braided from 3D printed liquid crystal elastomer fibers and thin heating threads. The unique hierarchical, braided knot structure offers amplified linear stroke, force rate, and damage-tolerance, as verified by both numerical simulations and experiments. In particular, the square knotted artificial muscle shows reliable cycles of actuation at 1Hz in 3000m depth underwater. Potential application is demonstrated by propelling a model boat. Looking ahead, the knotted artificial muscles can empower novel biomedical devices and soft robots to explore various environments, from inside human body to the mysterious deep sea.

Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension.

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

Sestrin2 and Sestrin3 protect spermatogenesis against heat-induced meiotic defects.

Heat stress (HS) induces testicular oxidative stress, impairs spermatogenesis, and increases the risk of male infertility. Recent studies have highlighted the antioxidative properties of the Sestrins family in reducing cellular oxidative damage. However, the role of Sestrins (Sestrin1, 2, and 3) in the testicular response to heat stress remains unclear. Here, we found that Sestrin 2 and 3 were highly expressed in the testis relative to Sestrin1. Then, the Sestrin2-/- and Sestrin3-/- mice were generated by CRISPR/Cas9 to investigate the role of them on spermatogenesis after HS. Our data showed that Sestrin2-/- and Sestrin3-/- mice testes exhibited more severe damage manifested by exacerbated loss of germ cells and higher levels of oxidative stress as compared to wild-type counterparts after HS. Notably, Sestrin2-/- and Sestrin3-/- mice underwent a remarkable increase in heat-induced spermatocyte apoptosis than that of controls. Mechanistically, the transcriptome landscape of spermatocytes and chromosome spreading showed that loss of Sestrin2 and Sestrin3 exacerbated meiotic failure by compromising DNA double-strand breaks (DSBs) repair after heat stress. Taken together, our work demonstrated a critical protective function of Sestrin2 and Sestrin3 in mitigating the impairments of spermatogenesis against heat stress.

Zhuang-Gu-Fang intervenes vasculogenic and osteogenic coupling in GK rats through Notch1/Noggin/VEGF pathway.

Background: Zhuang-Gu-Fang (ZGF) has been proved to treat osteoporosis in ovariectomized rats by increasing osteogenic related factors Leptin, Ghrelin and Peptide YY(PYY). However, the mechanism of ZGF in the treatment of diabetic osteoporosis (DOP) remains unclear. The aim of this study was to explore the therapeutic effect of ZGF on DOP and its potential molecular mechanism. Methods: Using GK rats as models, the pharmacodynamic effects of ZGF on bone loss were evaluated by hematoxylin-eosin (H&E) staining and micro-computed.tomography (micro-CT). The expression levels of CD31 and endomucin (Emcn) were detected by immunofluorescence to assess the role of ZGF in angiogenic osteogenic coupling. Finally, real-time quantitative PCR (RT-PCR) and Western Blot (WB)were used to detect the expression levels of osteogenic and angiogenesis-related genes and proteins Notch1, Noggin and vascular endothelial growth factor (VEGF). Results: Administration of ZGF demonstrated a significant mitigation of bone loss attributable to elevated glucose levels. H&E staining and micro-CT showed that ZGF notably improved the integrity of the trabecular and cortical bone microarchitecture. Moreover, ZGF was found to augment the density of type H vessels within the bone tissue, alongside elevating the expression levels of Osterix, a transcription factor pivotal for bone formation. Furthermore, our findings suggest that ZGF facilitates the activation of the Notch1/Noggin/VEGF pathway, indicating a potential mechanism through which ZGF exerts its osteoprotective effects. Conclusion: Our results suggest that ZGF potentially facilitates the formation of type H vessels through the Notch1/Noggin/VEGF pathway. This action not only enhances angiogenic-osteogenic coupling but also contributes to the improvement of bone structure and density. Consequently, ZGF emerges as a promising therapeutic agent for the prevention and management of DOP, offering a novel approach by leveraging angiogenesis-dependent osteogenesis.

Causal Relationship of Obstructive Sleep Apnea with Bone Mineral Density and the Role of BMI.

Background: Observational studies have yielded conflicting evidence concerning the relationships between obstructive sleep apnea (OSA) and bone mineral density (BMD). As the exact causal inferences remain inconclusive, we conducted a two-sample Mendelian randomization (MR) to identify the causal associations between OSA and BMD. Methods: Single-nucleotide polymorphisms associated with OSA were extracted from the FinnGen study. Summary statistics for 10 BMD measured at different age or skeletal sites were obtained from the publicly available IEU GWAS database. Inverse-variance weighted (IVW) method was chosen as the primary analysis, combined with several sensitivity analyses to evaluate the robustness of results. The study design included two-sample MR and network MR. Results: Our primary MR analysis revealed that genetically predicted OSA was positively linked to increased forearm BMD (ß = 0.24, 95% confidence interval [CI]: 0.06-0.41, p = 0.009) and heel BMD (ß=0.10, 95% CI = 0.02-0.18, p = 0.018), while no significant causal relationships were observed between OSA and total body BMD, lumbar spine BMD, or femoral neck BMD (all p > 0.05). Network MR suggests that OSA might act as a mediating factor in the effect of BMI on forearm BMD and heel BMD, with a mediated portion estimated at 73% and 84%, respectively. Conclusion: Our findings provide support for a causal relationship between genetically predicted OSA and increased forearm BMD and heel BMD. Furthermore, our results suggest that OSA may play a role in mediating the influence of BMI on BMD.

The effect of flywheel complex training with eccentric-overload on muscular adaptation in elite female volleyball players.

This study aimed to compare the effects of 8 weeks (24 sessions) between flywheel complex training with eccentric overload and traditional complex training of well-trained volleyball players on muscle adaptation, including hypertrophy, strength, and power variables. Fourteen athletes were recruited and randomly divided into the flywheel complex training with an eccentric-overload group (FCTEO, n = 7) and the control group (the traditional complex training group, TCT, n = 7). Participants performed half-squats using a flywheel device or Smith machine and drop jumps, with three sets of eight repetitions and three sets of 12 repetitions, respectively. The variables assessed included the muscle thickness at the proximal, mid, and distal sections of the quadriceps femoris, maximal half-squats strength (1RM-SS), squat jump (SJ), countermovement jump (CMJ), and three-step approach jump (AJ). In addition, a two-way repeated ANOVA analysis was used to find differences between the two groups and between the two testing times (pre-test vs. post-test). The indicators of the FCTEO group showed a significantly better improvement (p < 0.05) in CMJ (height: ES = 0.648, peak power: ES = 0.750), AJ (height: ES = 0.537, peak power: ES = 0.441), 1RM-SS (ES = 0.671) compared to the TCT group and the muscle thicknes at the mid of the quadriceps femoris (ES = 0.504) after FCTEO training. Since volleyball requires lower limb strength and explosive effort during repeated jumps and spiking, these results suggest that FCTEO affects muscular adaptation in a way that improves performance in well-trained female volleyball players.

Inactivation of Malic Enzyme 1 in Endothelial Cells Alleviates Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive cardiopulmonary disease with a high mortality rate. Although growing evidence has revealed the importance of dysregulated energetic metabolism in the pathogenesis of PH, the underlying cellular and molecular mechanisms are not fully understood. In this study, we focused on ME1 (malic enzyme 1), a key enzyme linking glycolysis to the tricarboxylic acid cycle. We aimed to determine the role and mechanistic action of ME1 in PH. METHODS: Global and endothelial-specific ME1 knockout mice were used to investigate the role of ME1 in hypoxia- and SU5416/hypoxia (SuHx)-induced PH. Small hairpin RNA and ME1 enzymatic inhibitor (ME1*) were used to study the mechanism of ME1 in pulmonary artery endothelial cells. Downstream key metabolic pathways and mediators of ME1 were identified by metabolomics analysis in vivo and ME1-mediated energetic alterations were examined by Seahorse metabolic analysis in vitro. The pharmacological effect of ME1* on PH treatment was evaluated in PH animal models induced by SuHx. RESULTS: We found that ME1 protein level and enzymatic activity were highly elevated in lung tissues of patients and mice with PH, primarily in vascular endothelial cells. Global knockout of ME1 protected mice from developing hypoxia- or SuHx-induced PH. Endothelial-specific ME1 deletion similarly attenuated pulmonary vascular remodeling and PH development in mice, suggesting a critical role of endothelial ME1 in PH. Mechanistic studies revealed that ME1 inhibition promoted downstream adenosine production and activated A2AR-mediated adenosine signaling, which leads to an increase in nitric oxide generation and a decrease in proinflammatory molecule expression in endothelial cells. ME1 inhibition activated adenosine production in an ATP-dependent manner through regulating malate-aspartate NADH (nicotinamide adenine dinucleotide plus hydrogen) shuttle and thereby balancing oxidative phosphorylation and glycolysis. Pharmacological inactivation of ME1 attenuated the progression of PH in both preventive and therapeutic settings by promoting adenosine production in vivo. CONCLUSIONS: Our findings indicate that ME1 upregulation in endothelial cells plays a causative role in PH development by negatively regulating adenosine production and subsequently dysregulating endothelial functions. Our findings also suggest that ME1 may represent as a novel pharmacological target for upregulating protective adenosine signaling in PH therapy.

Investigation of obesity and its related factors among Chinese medical staff: a cross-sectional pilot study.

BACKGROUND: Many studies have covered the prevalence of obesity in different populations. However, studies on the prevalence and predictors of obesity among medical staff are lacking. The aim of our study is to investigate the prevalence of obesity among medical staff and to identify the related predictors. METHODS: Using a snowballing recruitment strategy in the form of an electronic questionnaire, a cross-sectional survey was conducted among 1201 medical staff from cooperative hospitals between January and March 2022. We designed a questionnaire to investigate the participants' demographic, lifestyle, diet, physical activity, and work status. RESULTS: The overall prevalence of obesity was 8.5%, with males (13.7%) having a greater incidence than females (5.7%) (p < 0.001). Multiple logistic regression analyses showed that alcohol drinking (OR, 2.34; 95% CI 1.23-4.42, p = 0.01), sugar-sweetened beverages consumed > 3/week (OR, 2.50; 95% CI 1.02-6.15, p = 0.046), and working a night shift > 1/week (OR, 2.17; 95% CI 1.02-4.61, p = 0.043) were independent predictive factors for obesity in men. For women, having midnight snack having midnight snack (OR, 2.93;95% CI 1.24-6.96, p = 0.015), good sleep quality (OR, 4.47; 95% CI 1.10-21.70, p = 0.038), and working a night shift > 1/week (OR, 3.62; 95% CI 1.73-7.57, p = 0.001) were independently associated with obesity. CONCLUSIONS: Obesity presented a low prevalence among medical staff. Alcohol drinking, drinking sugar-sweetened beverages > 3/week, and night shift > 1/week predicted a higher risk of obesity in males. In females, having midnight snack, good sleep quality, and night shift > 1/week were independently associated with obesity. LEVEL OF EVIDENCE: V, descriptive study.

Anti-Cancer Effects of CDK4/6 Inhibitor LEE011 and Chemotherapy Drugs on Lymphocytic Leukemia L1210 Cells.

BACKGROUND/AIM: Chronic lymphocytic leukemia is a slowly-progressing disease in which symptoms often do not manifest until years after disease onset. In advanced stages, infection and bleeding are common. Past studies have shown that the interaction between CDK4/6 inhibitors and chemotherapy drugs can enhance the anti-tumor efficacy of drugs and limit toxicity. Therefore, in this study, the treatment effects of combining the CDK4/6 inhibitor LEE011 with chemotherapy drugs bendamustine or hydroxyurea were investigated in vitro. MATERIALS AND METHODS: The mouse lymphocytic leukemia cell line L1210 was treated with LEE011 combined with hydroxyurea or bendamustine. Western blot and flow cytometry were performed to elucidate the mechanisms behind tumor suppression. RESULTS: LEE011 combined with hydroxyurea or bendamustine significantly inhibited proliferation of L1210 cell lines in a concentration- and time-dependent manner as well as increased the arrest of cells in G1 and S phases. The combination of LEE011 with hydroxyurea also reduced the phosphorylation of Rb while increased the expression of total Rb protein. Furthermore, reduced expression of GPX4, which is a key protein in ferroptosis, indicates that the tumor suppression effects of this drug combination could involve ferroptosis. CONCLUSION: CDK4/6 inhibitor LEE011 treatment alone may not be a suitable treatment option for lymphocytic leukemia; however, our findings in vitro support the combination of LEE011 with chemotherapy drugs to enhance anti-tumor activity in lymphocytic leukemia.

Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and elevated mean pulmonary arterial pressure, resulting in right heart failure. METHODS: Here, we show that direct targeting of the endothelium to uncouple eNOS (endothelial nitric oxide synthase) with DAHP (2,4-diamino 6-hydroxypyrimidine; an inhibitor of GTP cyclohydrolase 1, the rate-limiting synthetic enzyme for the critical eNOS cofactor tetrahydrobiopterin) induces human-like, time-dependent progression of PH phenotypes in mice. RESULTS: Critical phenotypic features include progressive elevation in mean pulmonary arterial pressure, right ventricular systolic blood pressure, and right ventricle (RV)/left ventricle plus septum (LV+S) weight ratio; extensive vascular remodeling of pulmonary arterioles with increased medial thickness/perivascular collagen deposition and increased expression of PCNA (proliferative cell nuclear antigen) and alpha-actin; markedly increased total and mitochondrial superoxide production, substantially reduced tetrahydrobiopterin and nitric oxide bioavailabilities; and formation of an array of human-like vascular lesions. Intriguingly, novel in-house generated endothelial-specific dihydrofolate reductase (DHFR) transgenic mice (tg-EC-DHFR) were completely protected from the pathophysiological and molecular features of PH upon DAHP treatment or hypoxia exposure. Furthermore, DHFR overexpression with a pCMV-DHFR plasmid transfection in mice after initiation of DAHP treatment completely reversed PH phenotypes. DHFR knockout mice spontaneously developed PH at baseline and had no additional deterioration in response to hypoxia, indicating an intrinsic role of DHFR deficiency in causing PH. RNA-sequencing experiments indicated great similarity in gene regulation profiles between the DAHP model and human patients with PH. CONCLUSIONS: Taken together, these results establish a novel human-like murine model of PH that has long been lacking in the field, which can be broadly used for future mechanistic and translational studies. These data also indicate that targeting endothelial DHFR deficiency represents a novel and robust therapeutic strategy for the treatment of PH.

Pharmacology of bioactive compounds from plant extracts for improving non-alcoholic fatty liver disease through endoplasmic reticulum stress modulation: A comprehensive review.

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition with significant clinical implications. Emerging research indicates endoplasmic reticulum (ER) stress as a critical pathogenic factor governing inflammatory responses, lipid metabolism and insulin signal transduction in patients with NAFLD. ER stress-associated activation of multiple signal transduction pathways, including the unfolded protein response, disrupts lipid homeostasis and substantially contributes to NAFLD development and progression. Targeting ER stress for liver function enhancement presents an innovative therapeutic strategy. Notably, the natural bioactive compounds of plant extracts have shown potential for treating NAFLD by reducing the level of ER stress marker proteins and mitigating inflammation, stress responses, and de novo lipogenesis. However, owing to limited comprehensive reviews, the effectiveness and pharmacology of these bioactive compounds remain uncertain. Objectives: To address the abovementioned challenges, the current review categorizes the bioactive compounds of plant extracts by chemical structures and properties into flavonoids, phenols, terpenoids, glycosides, lipids and quinones and examines their ameliorative potential for NAFLD under ER stress. Methods: This review systematically analyses the literature on the interactions of bioactive compounds from plant extracts with molecular targets under ER stress, providing a holistic view of NAFLD therapy. Results: Bioactive compounds from plant extracts may improve NAFLD by alleviating ER stress; reducing lipid synthesis, inflammation, oxidative stress and apoptosis and enhancing fatty acid metabolism. This provides a multifaceted approach for treating NAFLD. Conclusion: This review underscores the role of ER stress in NAFLD and the potential of plant bioactive compounds in treating this condition. The molecular mechanisms by which plant bioactive compounds interact with their ER stress targets provide a basis for further exploration in NAFLD management.

Stiffness promotes cell migration, invasion, and invadopodia in nasopharyngeal carcinoma by regulating the WT-CTTN level.

Matrix stiffness potently promotes the malignant phenotype in various biological contexts. Therefore, identification of gene expression to participate in mechanical force signals transduced into downstream biochemical signaling will contribute substantially to the advances in nasopharyngeal carcinoma (NPC) treatment. In the present study, we detected that cortactin (CTTN) played an indispensable role in matrix stiffness-induced cell migration, invasion, and invadopodia formation. Advances in cancer research have highlighted that dysregulated alternative splicing contributes to cancer progression as an oncogenic driver. However, whether WT-CTTN or splice variants (SV1-CTTN or SV2-CTTN) regulate matrix stiffness-induced malignant phenotype is largely unknown. We proved that alteration of WT-CTTN expression modulated matrix stiffness-induced cell migration, invasion, and invadopodia formation. Considering that splicing factors might drive cancer progression through positive feedback loops, we analyzed and showed how the splicing factor PTBP2 and TIA1 modulated the production of WT-CTTN. Moreover, we determined that high stiffness activated PTBP2 expression. Taken together, our findings showed that the PTBP2-WT-CTTN level increases upon stiffening and then promotes cell migration, invasion, and invadopodia formation in NPC.