Hydrostatic pressure mediates epithelial-mesenchymal transition of cholangiocytes through RhoA/ROCK and TGF-ß/smad pathways.

Biomechanical cue within the tissue microenvironment is known to play a critical role in regulating cell behaviors and maintaining tissue homeostasis. As hydrostatic pressure often increases in biliary system under pathological states, we investigated the effect of the moderate elevation of the hydrostatic pressure on biliary epithelial cells, especially on the epithelial-mesenchymal transition (EMT). Human intrahepatic biliary epithelial cells were loaded to hydrostatic pressure using a commercial device. We found that loading the cells to 50 mmHg hydrostatic pressure induced obvious morphological changes and significantly upregulated vimentin, ZEB1, and pSmad2/3, fibronectin, and collagen 1α. All changes induced by hydrostatic pressure loading were effectively mitigated by either ROCK inhibitor (Y-27632) or ALK5 inhibitor (SB-431542). Our in vitro experimental data suggests that hydrostatic pressure loading induces EMT of cholangiocytes through RhoA/ROCK and TGF-ß/Smad pathways. Elevated hydrostatic pressure in biliary duct system under pathological states may promote the biliary epithelial cells shifting to profibrotic and mesenchymal characteristics.

Potassium peroxoborate: A sustained-released reactive oxygen carrier with enhanced PAHs contaminated soil remediation performance.

Seeking for a safe, efficient, inexpensive, and eco-friendly oxidizer is always a big challenge for in-situ chemical oxidation (ISCO) technology. This study adopted the potassium peroxoborate (PPB), a novel peroxide, for soil remediation for the first time. PPB based chemical oxidation system (PPB-CO) could efficiently degrade polycyclic aromatic hydrocarbons (PAHs) without other reagents added, reaching 72.1 %, 64.2 %, and 50.0 % removal rates for naphthalene, phenanthrene, and pyrene after 24 h reaction, respectively. The superior total PAHs removal efficiency (60.6 %) was 3.6-4.7 times higher than that of other commercial peroxides (2Na2CO3•3H2O, CaO2, and H2O2). Mechanism analysis revealed that varieties of reactive oxygen species (ROS) can be generated by PPB through Fenton-like or non-Fenton routines, including H2O2, perborates species, O2•-, •OH, and 1O2. The sustainable generation of H2O2 reduced the disproportionation effect of H2O2 by 86 %, significantly improving the utilization rate. Moreover, sandbox experiments and actual contaminated soil remediation experiments verified the feasibility of PPB-CO in a real polluted site. This work provides a novel strategy for effectively soil remediation, highlighting the selection and application of new oxidants.

Deficiency of the HGF/Met pathway leads to thyroid dysgenesis by impeding late thyroid expansion.

The mechanisms of bifurcation, a key step in thyroid development, are largely unknown. Here we find three zebrafish lines from a forward genetic screening with similar thyroid dysgenesis phenotypes and identify a stop-gain mutation in hgfa and two missense mutations in met by positional cloning from these zebrafish lines. The elongation of the thyroid primordium along the pharyngeal midline was dramatically disrupted in these zebrafish lines carrying a mutation in hgfa or met. Further studies show that MAPK inhibitor U0126 could mimic thyroid dysgenesis in zebrafish, and the phenotypes are rescued by overexpression of constitutively active MEK or Snail, downstream molecules of the HGF/Met pathway, in thyrocytes. Moreover, HGF promotes thyrocyte migration, which is probably mediated by downregulation of E-cadherin expression. The delayed bifurcation of the thyroid primordium is also observed in thyroid-specific Met knockout mice. Together, our findings reveal that HGF/Met is indispensable for the bifurcation of the thyroid primordium during thyroid development mediated by downregulation of E-cadherin in thyrocytes via MAPK-snail pathway.

Salvage haploidentical transplantation for graft failure after first haploidentical allogeneic stem cell transplantation: an updated experience.

Graft failure is a fatal complication following allogeneic stem cell transplantation where a second transplantation is usually required for salvage. However, there are no recommended regimens for second transplantations for graft failure, especially in the haploidentical transplant setting. We recently reported encouraging outcomes using a novel method (haploidentical transplantation from a different donor after conditioning with fludarabine and cyclophosphamide). Herein, we report updated outcomes in 30 patients using this method. The median time of the second transplantation was 96.5 (33-215) days after the first transplantation. Except for one patient who died at +19d and before engraftment, neutrophil engraftments were achieved in all patients at 11 (8-24) days, while platelet engraftments were achieved in 22 (75.8%) patients at 17.5 (9-140) days. The 1-year OS and DFS were 60% and 53.3%, and CIR and TRM was 6.7% and 33.3%, respectively. Compared with the historical group, neutrophil engraftment (100% versus 58.5%, p < 0.001) and platelet engraftment (75.8% versus 32.3%, p < 0.001) were better in the novel regimen group, and OS was also improved (60.0% versus 26.4%, p = 0.011). In conclusion, salvage haploidentical transplantation from a different donor using the novel regimen represents a promising option to rescue patients with graft failure after the first haploidentical transplantation.

A novel α,ß-unsaturated ketone inhibits leukemia cell growth as PARP1 inhibitor.

Leukemia is a malignant disease of the hematopoietic system, in which clonal leukemia cells accumulate and inhibit normal hematopoiesis in the bone marrow and other hematopoietic tissues as a result of uncontrolled proliferation and impaired apoptosis, among other mechanisms. In this study, the anti-leukemic effect of a compound (SGP-17-S) extracted from Chloranthus multistachys, a plant with anti-inflammatory, antibacterial and anti-tumor effects, was evaluated. The effect of SGP-17-S on the viability of leukemic cell was demonstrated by MTT assay, cell cycle, and apoptosis were assessed by flow cytometry using PI staining and Annexin V/PI double staining. Combinations of network pharmacology and cellular thermal shift assay (CETSA) with western blot were used to validate agents that act on leukemia targets. The results showed that SGP-17-S inhibited the growth of leukemia cells in a time- and dose-dependent manner. SGP-17-S blocked HEL cells in the G2 phase, induced apoptosis, decreased Bcl-2 and caspase-8 protein expression, and increased Bax and caspase-3 expression. In addition, CETSA revealed that PARP1 is an important target gene for the inhibition of HEL cell growth, and SGP-17-S exerted its action on leukemia cells by targeting PARP1. Therefore, this study might provide new solutions and ideas for the treatment of leukemia.

Decreasing the steroid rapidly may help to improve the clinical outcomes of patients with intestinal steroid-refractory acute graft-versus-host disease receiving basiliximab treatment.

Intestinal steroid refractory acute graft-versus-host disease (SR-aGVHD) is the major cause of mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). This retrospective cohort study aimed to identify the relationship between different steroid decreasing velocity and therapeutic response in patients with intestinal SR-aGVHD receiving basiliximab treatment, and also aimed to propose a reasonable steroid decreasing regimen for these patients. The median time for steroid dose decreasing to the 50% of initial dose and decreasing to the low-dose steroid for patients achieving ORR was 5 days and 12 days, respectively, which was both shorter than patients without achieving ORR. The ORR, NRM and survival in rapid and medium steroid decreasing group were all better than slow group. The cumulative incidence of ORR at any time was 90.4%, 78.1% and 62.3%, respectively, in rapid, medium, and slow group. The cumulative incidence of NRM at 1 year after basiliximab treatment was 18.7% (95% CI 11.3%-26.1%), 22.8% (95% CI 14.2%-31.4%) and 32.8% (95% CI 24.1%-41.5%), respectively, in rapid, medium, and slow group. The probability of OS at 1 year after basiliximab treatment was 76.9% (95% CI 68.9%-84.9%), 72.7% (95% CI 63.7%-81.7%), and 62.3% (95% CI 53.5%-71.1%), respectively, in rapid, medium, and slow group. Hence, it was helpful to decrease steroid to the 50% of initial dose ≤ 5 days and to the low-dose steroid ≤ 12 days after basiliximab treatment for intestinal SR-aGVHD patients, which may also be the reasonable steroid decrease protocol for these patients.

Association between dietary magnesium intake and gallstones: the mediating role of atherogenic index of plasma.

BACKGROUND: Dyslipidemia and abnormalities in cholesterol metabolism are commonly observed in individuals with gallstone disease. Previous research has demonstrated that dietary magnesium can influence lipid metabolism. The atherogenic index of plasma (AIP) has emerged as a novel lipid marker. This study aimed to examine the possible correlation between dietary magnesium intake and gallstones and the potential mediating role of AIP in US adults. METHODS: A total of 4,841 adults were included in this study from the National Health and Nutrition Examination Survey (NHANES) conducted from 2017 to 2020. A variety of statistical techniques such as logistic regression, subgroup analysis, smoothed curve fitting, and causal mediation analysis were utilized to analyze the information collected from the participants. RESULTS: In the fully adjusted model, a statistically noteworthy inverse relationship was observed between dietary magnesium intake and the presence of gallstones, as indicated by an odds ratio (OR) of 0.58 and a 95% confidence interval (CI) of (0.42, 0.81). Causal intermediary analysis revealed that the association between magnesium intake and gallstones was partially mediated by AIP, with a mediation ratio of 3.2%. CONCLUSION: According to this study, dietary magnesium intake had a significant linear negative association with the prevalence of gallstones, in which AIP played a mediating role. This discovery offers novel perspectives on the prevention and management of gallstones.

Nicaraven attenuates the acquired radioresistance of established tumors in mouse models via PARP inhibition.

Nicaraven has been reported to inhibit the activity of poly (ADP-ribose) polymerase (PARP). In this study, we investigated the probable ability of nicaraven to attenuate cancer radioresistance during fractionated radiotherapy. Tumor models were established in C57BL/6 mice and BALB/c nude mice by subcutaneous injection of Lewis mouse lung carcinoma cancer cells and A549 human lung cancer cells, respectively. When the tumors had grown to approximately 100 mm3, we initiated fractionated radiotherapy. Nicaraven or saline was administered immediately after each irradiation exposure. Compared to saline treatment, nicaraven administration significantly induced gamma-H2AX foci formation and cell apoptosis in tumors at 1 or 3 days after an additional challenge exposure to 10 Gy and inhibited tumor growth during the short-term follow-up period, suggesting increased radiosensitivity of cancer cells. Moreover, the expression of PARP in tumor tissue was decreased by nicaraven administration. Our data suggest that nicaraven likely attenuates the acquired radioresistance of cancers through PARP inhibition.

Global research trends and prospects of cellular metabolism in colorectal cancer.

BACKGROUND: An increasing number of studies have focused on the role of cellular metabolism in the development of colorectal cancer (CRC). However, no work is currently available to synthesize the field through bibliometrics. AIM: To analyze the development in the field of "glucose metabolism" (GM), "amino acid metabolism" (AM), "lipid metabolism" (LM), and "nucleotide metabolism" (NM) in CRC by visualization. METHODS: Articles within the abovementioned areas of GM, AM, LM and NM in CRC, which were published from January 1, 1991, to December 31, 2022, are retrieved from the Web of Science Core Collection and analyzed by CiteSpace 6.2.R4 and VOSviewer 1.6.19. RESULTS: The field of LM in CRC presented the largest number of annual publications and the fastest increase in the last decade compared with the other three fields. Meanwhile, China and the United States were two of the most prominent contributors in these four areas. In addition, Gang Wang, Wei Jia, Maria Notarnicola, and Cornelia Ulrich ranked first in publication numbers, while Jing-Yuan Fang, Senji Hirasawa, Wei Jia, and Charles Fuchs were the most cited authors on average in these four fields, respectively. "Gut microbiota" and "epithelial-mesenchymal transition" emerged as the newest burst words in GM, "gut microbiota" was the latest outburst word in AM, "metastasis", "tumor microenvironment", "fatty acid metabolism", and "metabolic reprogramming" were the up-to-date outbreaking words in LM, while "epithelial-mesenchymal transition" and "apoptosis" were the most recently occurring words in NM. CONCLUSION: Research in "cellular metabolism in CRC" is all the rage at the moment, and researchers are particularly interested in exploring the mechanism to explain the metabolic alterations in CRC. Targeting metabolic vulnerability appears to be a promising direction in CRC therapy.

Monoclonal neutralizing antibodies against SARS-COV-2 S protein.

Novel coronavirus pneumonia, also known as coronavirus disease 2019 (COVID-19), is caused by sub-severe acute respiratory syndrome type 2 coronavirus (SARS-CoV-2) infection. The spike (S) protein of SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors widely expressed on the surface of human cells leading to life-threatening respiratory infections. A serious hazard to human health is posed by the lack of particular treatment medications for this virus infection. We advocate the creation of high-affinity antibodies using the receptor binding domain (RBD) of S protein as a specific antigenic epitope to develop a drug that can precisely target therapy COVID-19 because SARS-CoV-2 infection of the host cells is dependent on S protein binding to ACE2. Finally, we obtained high-affinity antibodies 14F4HL and 14E3HL that have high affinity with RBD and well-drug-forming properties, suitable for further humanization studies. Thus, monoclonal antibodies that neutralize the S protein were identified in our study, which may provide new insights for the development of COVID-19 therapeutic drugs.

Effects of the plastic additive 2,4-di-tert-butylphenol on intestinal microbiota of zebrafish.

Plastic additives such as the antioxidant 2,4-di-tert-butylphenol (2,4-DTBP) have been widely detected in aquatic environments, over a wide range of concentrations reaching 300 µg/L in surface water, potentially threatening the health of aquatic organisms and ecosystems. However, knowledge of the specific effects of 2,4-DTBP on aquatic vertebrates is still limited. In this study, adult zebrafish were exposed to different concentrations of 2,4-DTBP (0, 0.01, 0.1 and 1.0 mg/L) for 21 days in the laboratory. The amplicon sequencing results indicated that the diversity and composition of the zebrafish gut microbiota were significantly changed by 2,4-DTBP, with a shift in the dominant flora to more pathogenic genera. Exposure to 2,4-DTBP at 0.1 and 1.0 mg/L significantly increased the body weight and length of zebrafish, suggesting a biological stress response. Structural assembly defects were also observed in the intestinal tissues of zebrafish exposed to 2,4-DTBP, including autolysis of intestinal villi, adhesions and epithelial detachment of intestinal villi, as well as inflammation. The transcriptional expression of some genes showed that 2,4-DTBP adversely affected protein digestion and absorption, glucose metabolism and lipid metabolism. These results are consistent with the PICRUSt2 functional prediction analysis of intestinal microbiota of zebrafish exposed to 2,4-DTBP. This study improves our understanding of the effects of 2,4-DTBP on the health of aquatic vertebrates and ecosystems.

Biomechanical Comparison of Anterior Cervical Corpectomy Decompression and Fusion, Anterior Cervical Discectomy and Fusion, and Anterior Controllable Antedisplacement and Fusion in the Surgical Treatment of Multilevel Cervical Spondylotic Myelopathy: A Finite Element Analysis.

PURPOSE: Multilevel cervical spondylotic myelopathy poses significant challenges in selecting optimal surgical approaches, warranting a comprehensive understanding of their biomechanical impacts. Given the lack of consensus regarding the most effective technique, this study aims to fill this critical knowledge gap by rigorously assessing and comparing the biomechanical properties of three distinct surgical interventions, including anterior controllable antedisplacement and fusion (ACAF), anterior cervical corpectomy decompression and fusion (ACCF), and anterior cervical discectomy and fusion (ACDF). The study offers pivotal insights to enhance treatment precision and patient outcomes. METHODS: The construction of the cervical spine model involved a detailed process using CT data, specialized software (Mimics, Geomagic Studio, and Hypermesh) and material properties obtained from prior studies. Surgical instruments were modeled (titanium mesh, anterior cervical plate, interbody cage, and self-tapping screws) to simulate three surgical approaches: ACAF, ACCF, and ACDF, each with specific procedures replicating clinical protocols. A 75-N follower load with 2 Nm was applied to simulate biomechanical effects. RESULTS: The range of motion decreased more after surgery for ACAF and ACDF than for ACCF, especially in flexion and lateral bending. ACCF have higher stress peaks in the fixation system than those of ACAF and ACDF, especially in flexion. The maximum von Mises stresses of the bone-screw interfaces at C3 of ACCF were higher than those of ACAF and ACDF. The maximum von Mises stresses of the bone-screw interfaces at C6 of ACDF were much higher than those of ACAF and ACCF. The maximum von Mises stresses of the grafts of ACCF and ACAF were much higher than those of ACDF. The maximum von Mises stresses of the endplate of ACCF were much higher than those of ACAF and ACDF. CONCLUSION: The ACAF and ACDF models demonstrated superior cervical reconstruction stability over the ACCF model. ACAF exhibited lower risks of internal fixation failure and cage subsidence compared to ACCF, making it a promising approach. However, while ACAF revealed improved stability over ACCF, higher rates of subsidence and internal fixation failure persisted compared to ACDF, suggesting the need for further exploration of ACAF's long-term efficacy and potential improvements in clinical outcomes.

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.

Study of cooling experiment and simulation for edible oil storage.

This paper proposes a refrigerant cooling method using an inner tube in a storage tank to improve the cooling performance and thermal uniformity during the storing of edible oil. With a prototype of an oil tank in Central Grain Reserve of Zhenjiang, the experimental oil tank was built in a scale of 50:1. Both natural and manual cooling experiments were carried out for the experimental tank. The manual cooling process involved two supplying modes for the refrigerant tube (top and bottom) and four different refrigerant temperatures (10 â„ƒ, 12 â„ƒ, 14 â„ƒ, 16 â„ƒ). The experimental results show that, compared with natural cooling, manual cooling can effectively reduce the temperature difference and thermal stratification between upper and lower layers. The temperature difference is 6.79 â„ƒ, 1.93 â„ƒ, and 3.67 â„ƒ for the natural cooling, manual top supplying, and manual bottom supplying mode, respectively. Furthermore, for the two manual modes, the cooling efficiency of bottom supplying is 21.4% higher than that of the top supplying, and the average oil temperature drops by 0.8-1 â„ƒ. Based on experimental results, different working conditions (20, 40, and 60 ml/s) were simulated to determine the optimal flow rate for bottom supplying mode. The simulation results indicate that the low flow rate (20 ml/s) corresponds to the best thermal uniformity, and the maximum temperature has no obvious change under different flow rate conditions. Therefore, it is not necessary to increase the flow rate to improve cooling efficiency considering the rising energy consumption.

Elevating sensing capability via dual-atom catalysts boosted luminol cathodic electrochemiluminescence.

BACKGROUND: The advancement of highly sensitive electrochemiluminescence (ECL) biosensors has garnered escalating interest over time. Owing to the distinctive physicochemical attributes, the signal amplification strategy facilitated by functional nanomaterials has achieved notable milestones. Single-atom catalysts (SACs), featuring atomically dispersed metal active sites, have garnered significant attention. SACs offer unprecedented control over active sites and surface structures at the atomic level. However, to fully harness their potential, ongoing efforts focus on strategies to enhance the catalytic performance of SACs, profoundly influencing both the sensitivity and selectivity of SACs-based sensing platforms. RESULTS: In this study, we focused on the synthesis and application of Fe-Co-PNC dual-atom catalysts (DACs) with the incorporation of phosphorus, aiming to enhance catalytic efficiency, particularly in the context of the oxygen reduction reaction (ORR) correlated cathodic luminol ECL. The synergistic effects arising from the combination of Fe and Co in DACs were explored by ECL emission. Comparative studies with Fe-PNC SACs highlighted the superior catalytic performance of Fe-Co-PNC DACs. The ECL sensing platform exhibited excellent sensitivity, which provided a fast detection of Trolox with a wide linear range (0.1 µM-1.0 mM) and a low detection limit (LOD) of 0.03 µM. The platform demonstrated remarkable reproducibility and long-term stability, showcasing its potential for practical biosensing applications. SIGNIFICANCE: This study introduced the novel concept of Fe-Co-PNC DACs. The demonstrated synergistic effects and enhanced catalytic efficiency of DACs offer new avenues for the rational design of advanced catalysts. The successful application in the sensitive detection of Trolox emphasizes their potential significance in biosensing. It not only expands our understanding of SACs but also opens doors for the development of efficient and stable catalysts with broader applications.

Catalytic Nanodots-Driven Pyroptosis Suppression in Nucleus Pulposus for Antioxidant Intervention of Intervertebral Disc Degeneration.

Low back pain resulting from intervertebral disc degeneration (IVDD) is a prevalent global concern; however, its underlying mechanism remains elusive. Single-cell sequencing analyses revealed the critical involvement of pyroptosis in IVDD. Considering the involvement of reactive oxygen species (ROS) as the primary instigator of pyroptosis and the lack of an efficient intervention approach, this study developed carbonized Mn-containing nanodots (MCDs) as ROS-scavenging catalytic biomaterials to suppress pyroptosis of nucleus pulposus (NP) cells to efficiently alleviate IVDD. Catalytic MCDs have superior efficacy in scavenging intracellular ROS and rescuing homeostasis in the NP microenvironment compared with N-acetylcysteine, a classical antioxidant. The data validates that pyroptosis plays a vital role in mediating the protective effects of catalytic MCDs against oxidative stress. Systematic in vivo assessments substantiate the effectiveness of MCDs in rescuing a puncture-induced IVDD rat model, further demonstrating their ability to suppress pyroptosis. This study highlights the potential of antioxidant catalytic nanomedicine as a pyroptosis inhibitor and mechanistically unveils an efficient strategy for the treatment of IVDD.

Electrogenerated Chemiluminescence Imaging of Single-Atom Nanocatalysts.

Single-atom catalysts (SACs), distinguished by their maximum atom efficiency and precise control over the coordination and electronic properties of individual atoms, show great promise in electrocatalysis. Gaining a comprehensive understanding of the electrochemical performance of SACs requires the screening of electron transfer process at micro/nano scale. This research pioneers the use of electrogenerated chemiluminescence microscopy (ECLM) to observe the electrocatalytic reactions at individual SACs. It boasts sensitivity at the single photon level and temporal resolution down to 100 ms, enabling real-time capture of the electrochemical behavior of individual SACs during potential sweeping. Leveraging the direct correlation between ECL emission and heterogeneous electron transfer processes, we introduced photon flux density for quantitative analysis, unveiling the electrocatalytic efficiency of individual SACs. This approach systematically reveals the relationship between SACs based on different metal atoms and their peroxidase (POD)-like activity. The outcomes contribute to a fundamental understanding of SACs and pave the way for designing SACs with diverse technological and industrial applications.

The perspective of cAMP/cGMP signaling and cyclic nucleotide phosphodiesterases in aortic aneurysm and dissection.

Aortic aneurysm (AA) and dissection (AD) are aortic diseases caused primarily by medial layer degeneration and perivascular inflammation. They are lethal when the rupture happens. Vascular smooth muscle cells (SMCs) play critical roles in the pathogenesis of medial degeneration, characterized by SMC loss and elastin fiber degradation. Many molecular pathways, including cyclic nucleotide signaling, have been reported in regulating vascular SMC functions, matrix remodeling, and vascular structure integrity. Intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are second messengers that mediate intracellular signaling transduction through activating effectors, such as protein kinase A (PKA) and PKG, respectively. cAMP and cGMP are synthesized by adenylyl cyclase (AC) and guanylyl cyclase (GC), respectively, and degraded by cyclic nucleotide phosphodiesterases (PDEs). In this review, we will discuss the roles and mechanisms of cAMP/cGMP signaling and PDEs in AA/AD formation and progression and the potential of PDE inhibitors in AA/AD, whether they are beneficial or detrimental. We also performed database analysis and summarized the results showing PDEs with significant expression changes under AA/AD, which should provide rationales for future research on PDEs in AA/AD.

Paris saponin VII promotes ferroptosis to inhibit breast cancer via Nrf2/GPX4 axis.

Breast cancer (BC) is one of the malignancies threatening the woman's health. Our study aims to explore the underlying mechanism behind the anti-tumor function of Paris saponin VII (PS VII) in BC. Xenografting experiment was conducted to monitor the tumor growth. The Ki67 and 4-HNE expression were analyzed via immunohistochemical assay. After different treatments, the cell viability, proliferation, invasion, and migration capacity of BC cells were measured by the CCK-8, colony formation, transwell, and wound healing assays, respectively. The ratio of GSH/GSSG was measured by the GSH/GSSG ratio detection assay kit. The lipid ROS and Fe2+ levels were quantified by flow cytometry analysis. The expressions of TFR1, ACSL4, Nrf2, and GPX4 were measured via western blotting. Compared with the Ctrl group, the tumor volumes, and Ki67 expression were markedly reduced in PS VII groups, and the BC cell viability was decreased by PS VII treatment in a dose-dependent manner. The colony numbers, invasive cells, and migration rates were also significantly decreased by PS VII treatment. Then, the Nrf2 as well as GPX4 expressions were decreased and TFR1 expression was increased by PS VII treatment in vitro and in vivo, while there was no difference in ACSL4 expression between Ctrl and PS VII groups. Moreover, the above effects of PS VII could not be observed in GPX4 knockdown cells. PS VII can promote ferroptosis to inhibit BC via the Nrf2/GPX4 axis, which innovatively suggests the pro-ferroptosis effect and therapeutic potential of PS VII in BC.

Peripheral blood stem cell transplantation from haploidentical related donor could achieve satisfactory clinical outcomes for intermediate- or high-risk adult acute myeloid leukemia patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most important curative method for intermediate- and high-risk adult acute myeloid leukemia (AML) patients. We aimed to identify the clinical outcomes of haploidentical related donor (HID) peripheral blood stem cell transplantation (PBSCT) who receiving peripheral blood (G-PB) harvest, and the patients receiving bone marrow (BM) plus G-PB harvest (BM + PB) as grafts were enrolled as control. The engraftments of neutrophil and platelet in G-PB group were both faster than those in BM + PB group. The cumulative incidences of grade II-IV acute graft-versus-host disease (aGVHD), and moderate to severe chronic GVHD (cGVHD) were all comparable between G-PB and BM + PB groups. The cumulative incidence of relapse and non-relapse mortality at 3 years after HID HSCT was 12.6% versus 13.7% (p = 0.899) and 3.6% versus 7.3% (p = 0.295), respectively, in G-PB and BM + PB group. While the probabilities of GVHD-free/relapse-free survival, leukemia-free survival, and overall survival at 3 years after HID HSCT were 60.6% versus 53.4% (p = 0.333), 83.8% versus 79.0% (p = 0.603), and were 87.3% versus 82.9% (p = 0.670), respectively. We confirmed the safety and efficacy of HID PBSCT in intermediate- and high-risk AML patients in a large cohort.