Sacubitril/valsartan reversal of left ventricular remodeling is associated with improved hemodynamics in resistant hypertension.

BACKGROUND: Sacubitril/valsartan (S/V) has been shown to be an effective antihypertensive drug combination. However, its therapeutic effects on blood pressure (BP), hemodynamics, and left ventricular (LV) remodeling in resistant hypertension (RHTN) remain unclear. METHODS: Eighty-six patients completed this self-control study, during which olmesartan was administered within the first 8 weeks (phase 1), followed by S/V within the second 8 weeks (phase 2), with nifedipine and hydrochlorothiazide taken as background medications. Office BP, echocardiography, and hemodynamics assessment using impedance cardiography were performed at baseline and at the eighth and sixteenth weeks. RESULTS: The reduction in office BP was larger in phase 2 than in phase 1 (19.59/11.66 mmHg vs. 2.88/1.15 mmHg). Furthermore, the treatment in phase 2 provided greater reductions in systemic vascular resistance index (SVRI) and thoracic blood saturation ratio (TBR), with differences between the two phases of -226.59 (-1212.80 to 509.55) dyn·s/cm5/m2 and -0.02 (-0.04 to 0.02). Switching from olmesartan to S/V also significantly reduced E/E', LV mass index, LV end-diastolic volume index, and LV end-systolic volume index (all P < 0.05). Decreases in arterial stiffness, SVRI, and TBR were correlated with changes in indicators of LV remodeling (all P < 0.05). This correlation persisted even after adjusting for confounders including changes in BP. CONCLUSIONS: Switching from olmesartan to S/V effectively lowered BP and reversed ventricular remodeling in RHTN. In addition, hemodynamic improvement was also observed. Changes in hemodynamics played an important role in reversing LV remodeling of S/V, and were independent of its antihypertensive effect.

KAT7 enhances the proliferation and metastasis of head and neck squamous carcinoma by promoting the acetylation level of LDHA.

Lysine acetyltransferase 7 (KAT7), a histone acetyltransferase, has recently been identified as an oncoprotein and has been implicated in the development of various malignancies. However, its specific role in head and neck squamous carcinoma (HNSCC) has not been fully elucidated. Our study revealed that high expression of KAT7 in HNSCC patients is associated with poor survival prognosis and silencing KAT7 inhibits the Warburg effect, leading to reduced proliferation, invasion, and metastatic potential of HNSCC. Further investigation uncovered a link between the high expression of KAT7 in HNSCC and tumor-specific glycolytic metabolism. Notably, KAT7 positively regulates Lactate dehydrogenase A (LDHA), a key enzyme in metabolism, to promote lactate production and create a conducive environment for tumor proliferation and metastasis. Additionally, KAT7 enhances LDHA activity and upregulates LDHA protein expression by acetylating the lysine 118 site of LDHA. Treatment with WM3835, a KAT7 inhibitor, effectively suppressed the growth of subcutaneously implanted HNSCC cells in mice. In conclusion, our findings suggest that KAT7 exerts pro-cancer effects in HNSCC by acetylating LDHA and may serve as a potential therapeutic target. Inhibiting KAT7 or LDHA expression holds promise as a therapeutic strategy to suppress the growth and progression of HNSCC.

Thermal-to-Electrical Conversion Based on Salinity Gradient Driven by Evaporation.

Constructing concentration differences between anions and cations at the ends of an ionic conductor is an effective strategy in electricity generation for powering wearable devices. Temperature gradient or salinity gradient is the driving force behind such devices. But their corresponding power generation devices are greatly limited in actual application due to their complex structure and harsh application conditions. In this study, a novel ionic concentration gradient electric generator based on the evaporation difference of the electrolyte is proposed. The device can be constructed without the need for semipermeable membranes, and operation does not need to build a temperature difference. As a demonstration, a PVA-Na ionic hydrogel is prepared as an electrolyte for the device and achieved a thermovoltage of more than 200 mV and an energy density of 77.94 J m-2 at 323 K. Besides, the device exhibits the capability to sustain a continuous voltage output for a duration exceeding 1500 min, as well as enabling charging and discharging cycles for 100 iterations. For practical applications, a module comprising 16 sub-cells is constructed and successfully utilized to directly power a light-emitting diode. Wearable devices and their corresponding cell modules are also developed to recycle body heat.

Patterns of use of advanced wound matrices in the Veterans Administration clinics.

Chronic wounds are a common and costly health issue affecting millions of individuals in the United States, particularly those with underlying conditions such as diabetes, venous insufficiency, and peripheral artery disease. When standard treatments fail, advanced wound care therapies, such as skin substitutes, are often applied. However, the clinical effectiveness, indications, and comparative benefits of these therapies have not been well established. In this study, we report on the usage of both acellular and cellular, single and bilayer, natural and synthetic, dermal, and epidermal skin substitutes in a VA hospital system. We performed a retrospective chart review to understand the ordering and usage patterns of advanced wound therapies for patients with chronic wounds at the VA Northern California Health Care System. We examined types of products being recommended, categories of users recommending the products, indications for orders, and rate of repeated orders. Neuropathic, venous, or pressure ulcers were the main indications for using advanced wound matrices. Only 15.6% of patients for whom the matrices were ordered had supporting laboratory tests. Exactly 34.3% of the ordered matrices were not applied. And the use of wound matrices resulted in increased costs per patient visit of $1018-$3450. Our study sheds light on the usage patterns of these therapies in a VA healthcare facility and highlights the need for more robust evidence-based studies to determine the true benefits, efficacy, and cost-effectiveness of these innovative treatment options.

Hsa-LINC02418/mmu-4930573I07Rik regulated by METTL3 dictates anti-PD-L1 immunotherapeutic efficacy via enhancement of Trim21-mediated PD-L1 ubiquitination.

BACKGROUND: Limited response to programmed death ligand-1 (PD-L1)/programmed death 1 (PD-1) immunotherapy is a major hindrance of checkpoint immunotherapy in non-small cell lung cancer (NSCLC). The abundance of PD-L1 on the tumor cell surface is crucial for the responsiveness of PD-1/PD-L1 immunotherapy. However, the negative control of PD-L1 expression and the physiological significance of the PD-L1 inhibition in NSCLC immunotherapy remain obscure. METHODS: Bioinformatics analysis was performed to profile and investigate the long non-coding RNAs that negatively correlated with PD-L1 expression and positively correlated with CD8+T cell infiltration in NSCLC. Immunofluorescence, in vitro PD-1 binding assay, T cell-induced apoptosis assays and in vivo syngeneic mouse models were used to investigate the functional roles of LINC02418 and mmu-4930573I07Rik in regulating anti-PD-L1 therapeutic efficacy in NSCLC. The molecular mechanism of LINC02418-enhanced PD-L1 downregulation was explored by immunoprecipitation, RNA immunoprecipitation (RIP), and ubiquitination assays. RIP, luciferase reporter, and messenger RNA degradation assays were used to investigate the m6A modification of LINC02418 or mmu-4930573I07Rik expression. Bioinformatics analysis and immunohistochemistry (IHC) verification were performed to determine the significance of LINC02418, PD-L1 expression and CD8+T cell infiltration. RESULTS: LINC02418 is a negative regulator of PD-L1 expression that positively correlated with CD8+T cell infiltration, predicting favorable clinical outcomes for patients with NSCLC. LINC02418 downregulates PD-L1 expression by enhancing PD-L1 ubiquitination mediated by E3 ligase Trim21. Both hsa-LINC02418 and mmu-4930573I07Rik (its homologous RNA in mice) regulate PD-L1 therapeutic efficacy in NSCLC via Trim21, inducing T cell-induced apoptosis in vitro and in vivo. Furthermore, METTL3 inhibition via N6-methyladenosine (m6A) modification mediated by YTHDF2 reader upregulates hsa-LINC02418 and mmu-4930573I07Rik. In patients with NSCLC, LINC02418 expression is inversely correlated with PD-L1 expression and positively correlated with CD8+T infiltration. CONCLUSION: LINC02418 functions as a negative regulator of PD-L1 expression in NSCLC cells by promoting the degradation of PD-L1 through the ubiquitin-proteasome pathway. The expression of LINC02418 is regulated by METTL3/YTHDF2-mediated m6A modification. This study illuminates the underlying mechanisms of PD-L1 negative regulation and presents a promising target for improving the effectiveness of anti-PD-L1 therapy in NSCLC.

First-Principles Study on Si Atom Diffusion Behavior in Ni-Based Superalloys.

The Si atom diffusion behavior in Ni-based superalloys was evaluated based on first-principles calculations. Also, the site occupation of Si atoms as the melting point depressant elements in Cr, Mo, and W atom doped γ-Ni and γ'-Ni3Fe supercells was discussed and Si atom diffusion behaviors between both adjacent octahedral interstices were analyzed. Calculation results indicated that formation enthalpy (∆Hf) was decreased, stability was improved by doping alloying elements Cr, Mo, and W in γ-Ni and γ'-Ni3Fe supercells, Si atoms were more inclined to occupy octahedral interstices and the diffusion energy barrier was increased by increasing the radius of the doped alloy element. Especially, two diffusion paths were available for Si atoms in the γ'-Ni3Fe and Si diffusion energy barrier around the shared Fe atoms between adjacent octahedral interstices and was significantly lower than that around the shared Ni atoms. The increase of interaction strength between the doped M atom/octahedron constituent atom and Si atom increased Si atom diffusion and decreased the diffusion energy barrier. The Si atom diffusion behavior provides a theoretical basis for the phase structure evolution in wide-gap brazed joints.

Evolution and Variations of the Ovine Model of Spina Bifida.

Spina bifida is the most common congenital anomaly of the central nervous system and the first non-fatal fetal lesions to be addressed by fetal intervention. While research in spina bifida has been performed in rodent, nonhuman primate, and canine models, sheep have been a model organism for the disease. This review summarizes the history of development of the ovine model of spina bifida, previous applications, and translation into clinical studies. Initially used by Meuli et al. [Nat Med. 1995;1(4):342-7], fetal myelomeningocele defect creation and in utero repair demonstrated motor function preservation. The addition of myelotomy in this model can reproduce hindbrain herniation malformations, which is the leading cause of mortality and morbidity in humans. Since inception, the ovine models have been validated numerous times as the ideal large animal model for fetal repair, with both locomotive scoring and spina bifida defect scoring adding to the rigor of this model. The ovine model has been used to study different methods of myelomeningocele defect repair, the application of various tissue engineering techniques for neuroprotection and bowel and bladder function. The results of these large animal studies have been translated into human clinical trials including Management of Meningocele Study (MOMS) trial that established current standard of care for prenatal repair of spina bifida defects, and the ongoing trials including the Cellular Therapy for In Utero Repair of Myelomeningocele (CuRe) trial using a stem cell patch for repair. The advancement of these life savings and life-altering therapies began in sheep models, and this notable model continues to be used to further the field including current work with stem cell therapy.

SIRT2 Deficiency Aggravates Diet-Induced Nonalcoholic Fatty Liver Disease through Modulating Gut Microbiota and Metabolites.

Non-alcoholic fatty liver disease (NAFLD), characterized by excessive lipid accumulation in hepatocytes, is an increasing global healthcare burden. Sirtuin 2 (SIRT2) functions as a preventive molecule for NAFLD with incompletely clarified regulatory mechanisms. Metabolic changes and gut microbiota imbalance are critical to the pathogenesis of NAFLD. However, their association with SIRT2 in NAFLD progression is still unknown. Here, we report that SIRT2 knockout (KO) mice are susceptible to HFCS (high-fat/high-cholesterol/high-sucrose)-induced obesity and hepatic steatosis accompanied with an aggravated metabolic profile, which indicates SIRT2 deficiency promotes NAFLD-NASH (nonalcoholic steatohepatitis) progression. Under palmitic acid (PA), cholesterol (CHO), and high glucose (Glu) conditions, SIRT2 deficiency promotes lipid deposition and inflammation in cultured cells. Mechanically, SIRT2 deficiency induces serum metabolites alteration including upregulation of L-proline and downregulation of phosphatidylcholines (PC), lysophosphatidylcholine (LPC), and epinephrine. Furthermore, SIRT2 deficiency promotes gut microbiota dysbiosis. The microbiota composition clustered distinctly in SIRT2 KO mice with decreased Bacteroides and Eubacterium, and increased Acetatifactor. In clinical patients, SIRT2 is downregulated in the NALFD patients compared with healthy controls, and is associated with exacerbated progression of normal liver status to NAFLD to NASH in clinical patients. In conclusion, SIRT2 deficiency accelerates HFCS-induced NAFLD-NASH progression by inducing alteration of gut microbiota and changes of metabolites.

Enhanced external counterpulsation ameliorates endothelial dysfunction and elevates exercise tolerance in patients with coronary artery disease.

Purpose: Enhanced external counterpulsation (EECP) is a new non-drug treatment for coronary artery disease (CAD). However, the long-term effect of EECP on endothelial dysfunction and exercise tolerance, and the relationship between the changes in the endothelial dysfunction and exercise tolerance in the patients with coronary heart disease are still unclear. Methods: A total of 240 patients with CAD were randomly divided into EECP group (n = 120) and control group (n = 120). All patients received routine treatment of CAD as the basic therapy. Patients in the EECP group received 35 1-h daily sessions of EECP during 7 consecutive weeks while the control group received the same treatment course, but the cuff inflation pressure was 0-10 mmHg. Peak systolic velocity (PSV), end diastolic velocity (EDV), resistance index (RI), and inner diameter (ID) of the right carotid artery were examined using a Color Doppler Ultrasound and used to calculate the fluid shear stress (FSS). Serum levels of human vascular endothelial cell growth factor (VEGF), vascular endothelial cell growth factor receptor 2 (VEGFR2), and human angiotensin 2 (Ang2) were determined by enzyme-linked immunosorbent assay (ELISA). Exercise load time, maximal oxygen uptake (VO2max ), metabolic equivalent (METs), anaerobic threshold (AT), peak oxygen pulse (VO2max/HR) were assessed using cardiopulmonary exercise tests. Results: After 1 year follow-up, the EDV, PSV, ID, and FSS were significantly increased in the EECP group (P < 0.05 and 0.01, respectively), whereas there were no significant changes in these parameters in the control group. The serum levels of VEGF and VEGFR2 were elevated in the EECP and control groups (all P < 0.05). However, the changes in VEGF and VEGFR2 were significantly higher in the EECP group than in the control group (P < 0.01). The serum level of Ang2 was decreased in the EECP group (P < 0.05) and no obvious changes in the control group. As for exercise tolerance of patients, there were significant increases in the exercise load time, VO2max, VO2max/HR, AT and METs in the EECP group (all P < 0.05) and VO2max and METs in the control group (all P < 0.05). Correlation analyses showed a significant and positive correlations of VEGF and VEGFR2 levels with the changes in FSS (all P < 0.001). The correlations were still remained even after adjustment for confounders (all Padjustment < 0.001). Linear regression displays the age, the medication of ACEI (angiotensin-converting enzyme inhibitors) or ARB (angiotensin receptor blockers), the diabetes and the changes in VEGF and VEGFR2 were positively and independently associated with the changes in METs after adjustment for confounders (all Padjustment < 0.05). Conclusion: The data of our study suggested that EECP is a useful therapeutic measurement for amelioration of endothelial dysfunction and long-term elevation of exercise tolerance for patients with coronary heart disease. Clinical trial registration: [http://www.chictr.org.cn/], identifier [ChiCTR1800020102].

DNMT3B-mediated FAM111B methylation promotes papillary thyroid tumor glycolysis, growth and metastasis.

Over the past decades, the incidence of thyroid cancer (TC) rapidly increased all over the world, with the papillary thyroid cancer (PTC) accounting for the vast majority of TC cases. It is crucial to investigate novel diagnostic and therapeutic targets for PTC and explore more detailed molecular mechanisms in the carcinogenesis and progression of PTC. Based on the TCGA and GEO databases, FAM111B is downregulated in PTC tissues and predicts better prognosis in PTC patients. FAM111B suppresses the growth, migration, invasion and glycolysis of PTC both in vitro and in vivo. Furthermore, estrogen inhibits FAM111B expression by DNMT3B methylation via enhancing the recruitment of DNMT3B to FAM111B promoter. DNMT3B-mediated FAM111B methylation accelerates the growth, migration, invasion and glycolysis of PTC cells. In clinical TC patient specimens, the expression of FAM111B is inversely correlated with the expressions of DNMT3B and the glycolytic gene PGK1. Besides, the expression of FAM111B is inversely correlated while DNMT3B is positively correlated with glucose uptake in PTC patients. Our work established E2/DNMT3B/FAM111B as a crucial axis in regulating the growth and progression of PTC. Suppression of DNMT3B or promotion of FAM111B will be potential promising strategies in the estrogen induced PTC.

SIRT3 attenuates coronary atherosclerosis in diabetic patients by regulating endothelial cell function.

BACKGROUND: This study aimed to explore the relationship between the Sirtuin 3 (SIRT3) gene and endothelial cell dysfunction, contributing to the progression of coronary atherosclerosis driven by hyperglycemia. METHODS: We measured serum SIRT3 levels using enzyme-linked immunosorbent assay in 95 patients with type 2 diabetes mellitus (T2DM) who underwent diagnostic coronary angiography. The patients were divided into two groups according to the presence (n = 45) or absence (n = 50) of coronary artery disease (CAD). Human aortic endothelial cells (HAECs) grown in vitro in a medium with various concentrations of glucose (5.5, 11, 16.5, 22, 27.5, 33, and 38.5 mM) for 24 h were assessed for protein expression of SIRT3, peroxisome proliferator-activated receptor alpha (PPAR-α), endothelial nitric oxide (NO) synthase (eNOS), and inducible NO synthase (iNOS) using Western blot analysis. HAECs were subjected to SIRT3 overexpression or inhibition through SIRT3 adenovirus and siRNA transfection. RESULTS: Serum SIRT3 levels were significantly lower in T2DM patients with CAD than in those without CAD (p = 0.048). The in vitro results showed that HG significantly increased SIRT3, PPAR-α, and eNOS protein expression in a concentration-dependent manner. Moreover, iNOS expression was decreased in HAECs in response to HG. Reduced PPAR-α and eNOS levels and increased iNOS levels were observed in SIRT3 silenced HAECs cells. In contrast, SIRT3 overexpression significantly improved PPAR-α and eNOS expression and suppressed iNOS expression. CONCLUSION: SIRT3 was associated with the progression of atherosclerosis in T2DM patients through upregulation of PPAR-α and eNOS and downregulation of iNOS, which are involved in endothelial dysfunction under hyperglycemic conditions.

Ursolic Acid Ameliorates the Injury of H9c2 Cells Caused by Hypoxia and Reoxygenation Through Mediating CXCL2/NF-κB Pathway.

Ursolic acid (UA) has been reported to possess several biological benefits, such as anti-cancer, anti-inflammation, antibacterial, and neuroprotective functions. This study detects the function and molecular mechanism of UA in H9c2 cells under hypoxia and reoxygenation (H/R) conditions.Under H/R stimulation, the effects of UA on H9c2 cells were examined using ELISA and western blot assays. The Comparative Toxicogenomics Database was employed to analyze the target molecule of UA. Small interfering RNA was used to knock down CXCL2 expression, further exploring the function of CXCL2 in H/R-induced H9c2 cells. The genes related to the nuclear factor-kappa B (NF-κB) pathway were assessed using western blot analysis.Significant effects of UA on H/R-induced H9c2 cell damage were observed, accompanied by reduced inflammation and oxidative stress injury. Additionally, the increased level of CXCL2 in H/R-induced H9c2 cells was reduced after UA stimulation. Moreover, CXCL2 knockdown strengthened the beneficial effect of UA on H/R-induced H9c2 cells. HY-18739, an activator of the NF-κB pathway, can increase CXCL2 expression. Moreover, the increased levels of p-P65 NF-κB and p-IκBα in H/R-induced H9c2 cells were remarkably attenuated by UA treatment.In summary, the results indicated that UA may alleviate the damage of H9c2 cells by targeting the CXCL2/NF-κB pathway under H/R conditions.

Spina Bifida: A Review of the Genetics, Pathophysiology and Emerging Cellular Therapies.

Spina bifida is the most common congenital defect of the central nervous system which can portend lifelong disability to those afflicted. While the complete underpinnings of this disease are yet to be fully understood, there have been great advances in the genetic and molecular underpinnings of this disease. Moreover, the treatment for spina bifida has made great advancements, from surgical closure of the defect after birth to the now state-of-the-art intrauterine repair. This review will touch upon the genetics, embryology, and pathophysiology and conclude with a discussion on current therapy, as well as the first FDA-approved clinical trial utilizing stem cells as treatment for spina bifida.

Ursolic acid protects against anoxic injury in cardiac microvascular endothelial cells by regulating intercellular adhesion molecule-1 and toll-like receptor 4/MyD88/NF-κB pathway.

BACKGROUND: Cardiac microvascular endothelial cells (CMECs) are rapidly damaged after myocardial ischemia or hypoxia. In this study, we intend to explore whether ursolic acid (UA) can protect CMECs against hypoxia/reoxygenation (H/R) injury and to detect related molecular mechanism. METHODS: CMECs were subjected to H/R condition in the absence or presence of UA. Cell behaviors were measured by Cell Counting Kit-8, transwell, ELISA and western blot assays. siRNA was applied to reduce ICAM1 expression, then the effect of co-treatment of UA and si-ICAM1 on CMECs has been detected by biological experiments. RESULTS: Under H/R stimulation, the proliferation and migration of CMECs were inhibited, as well as the inflammation and oxidative stress were enhanced. UA treatment obviously reversed these H/R-induced injuries and reduced ICAM1 expression. Moreover, knockdown of ICAM1 could alleviate the H/R-induced injuries and strengthen the protective effect of UA on CMECs under H/R condition. Additionally, the protein levels of TLR4, MyD88 and p-P65 NF-κB were obviously increased after H/R stimulation, whereas the addition of UA could alter the phenomena by reducing TLR4, MyD88, and p-P65 NF-κB expression. CONCLUSIONS: Our results insinuated that UA could alleviate H/R-induced injuries in CMECs by regulating ICAM1 and TLR4/MyD88/NF-κB pathway.

Identification and prognostic analysis of biomarkers to predict the progression of pancreatic cancer patients.

BACKGROUND: Pancreatic cancer (PC) is a malignancy with a poor prognosis and high mortality. Surgical resection is the only "curative" treatment. However, only a minority of patients with PC can obtain surgery. Improving the overall survival (OS) rate of patients with PC is still a major challenge. Molecular biomarkers are a significant approach for diagnostic and predictive use in PCs. Several prediction models have been developed for patients newly diagnosed with PC that is operable or patients with advanced and metastatic PC; however, these models require further validation. Therefore, precise biomarkers are urgently required to increase the efficiency of predicting a disease-free survival (DFS), OS, and sensitivity to immunotherapy in PC patients and to improve the prognosis of PC. METHODS: In the present study, we first evaluated the highly and selectively expressed targets in PC, using the GeoMxTM Digital Spatial Profiler (DSP) and then, we analyzed the roles of these targets in PCs using TCGA database. RESULTS: LAMB3, FN1, KRT17, KRT19, and ANXA1 were defined as the top five upregulated targets in PC compared with paracancer. The TCGA database results confirmed the expression pattern of LAMB3, FN1, KRT17, KRT19, and ANXA1 in PCs. Significantly, LAMB3, FN1, KRT19, and ANXA1 but not KRT17 can be considered as biomarkers for survival analysis, univariate and multivariate Cox proportional hazards model, and risk model analysis. Furthermore, in combination, LAMB3, FN1, KRT19, and ANXA1 predict the DFS and, in combination, LAMB3, KRT19, and ANXA1 predict the OS. Immunotherapy is significant for PCs that are inoperable. The immune checkpoint blockade (ICB) analysis indicated that higher expressions of FN1 or ANXA1 are correlated with lower ICB response. In contrast, there are no significant differences in the ICB response between high and low expression of LAMB3 and KRT19. CONCLUSIONS: In conclusion, LAMB3, FN1, KRT19, and ANXA1 are good predictors of PC prognosis. Furthermore, FN1 and ANXA1 can be predictors of immunotherapy in PCs.

LINC00244 suppresses cell growth and metastasis in hepatocellular carcinoma by downregulating programmed cell death ligand 1.

The role of programmed cell death ligand 1 (PD-L1) in suppressing antitumor immune responses has been widely reported, and recent studies showed that PD-L1 also plays an important role in epithelial-mesenchymal transition (EMT), determination of tumor cell phenotypes, metastasis, and drug resistance. Long non-coding RNAs (lncRNAs) are involved in a variety of epigenetic regulatory processes. The tumorigenesis and development of most cancers cannot be studied separately from their regulation by lncRNAs. To explore the epigenetic regulation of PD-L1, we identified an lncRNA, LINC00244, which reduced PD-L1 expression and predicted good clinical outcomes in hepatocellular carcinoma (HCC). LINC00244 inhibited the proliferation, invasion, and metastasis of HCC by downregulating PD-L1 expression. In addition, low LINC00244 expression activated epithelial-mesenchymal transition (EMT) pathways and facilitated the rapid growth and metastasis of HCC cells. Thus, LINC00244 is a potential therapeutic target for HCC.

The Evaluation of Meloxicam Nanocrystals by Oral Administration with Different Particle Sizes.

Meloxicam (MLX) is a non-steroidal anti-inflammatory drug used to treat rheumatoid arthritis and osteoarthritis. However, its poor water solubility limits the dissolution process and influences absorption. In order to solve this problem and improve its bioavailability, we prepared it in nanocrystals with three different particle sizes to improve solubility and compare the differences between various particle sizes. The nanocrystal particle sizes were studied through dynamic light scattering (DLS) and laser scattering (LS). Transmission electron microscopy (TEM) was used to characterize the morphology of nanocrystals. The sizes of meloxicam-nanocrystals-A (MLX-NCs-A), meloxicam-nanocrystals-B (MLX-NCs-B), and meloxicam-nanocrystals-C (MLX-NCs-C) were 3.262 ± 0.016 µm, 460.2 ± 9.5 nm, and 204.9 ± 2.8 nm, respectively. Molecular simulation was used to explore the distribution and interaction energy of MLX molecules and stabilizer molecules in water. The results of differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) proved that the crystalline state did not change in the preparation process. Transport studies of the Caco-2 cell model indicated that the cumulative degree of transport would increase as the particle size decreased. Additionally, plasma concentration-time curves showed that the AUC0-∞ of MLX-NCs-C were 3.58- and 2.92-fold greater than those of MLX-NCs-A and MLX-NCs-B, respectively. These results indicate that preparing MLX in nanocrystals can effectively improve the bioavailability, and the particle size of nanocrystals is an important factor in transmission and absorption.

Design of thin-structured-light projection system for small-height measurement.

A thin-structured light projection system with simple setup is proposed and applied to small-height measurement. In this system, the design of structured light pattern is carried out on the computer. The structure, color, geometric dimension, motion mode, projection brightness, contrast, and other attributes of the pattern can be edited easily. The optical system with zoom function is designed, which can output thin-structured-light fringe with a minimum width of 10 µm. The camera and microscope are used to construct a vision system, which is used to capture the pattern of structured light. The three-dimensional (3D) shape reconstruction is realized by analyzing the pattern of structured light. The results show that this system can project a small width of thin-structured light pattern, which is very suitable for 3D shape reconstruction of microscopic objects with the small-height of tens of microns to hundreds of microns.

Systematic investigation of the aza-Cope reaction for fluorescence imaging of formaldehyde in vitro and in vivo.

Increasing evidence has highlighted the endogenous production of formaldehyde (FA) in a variety of fundamental biological processes and its involvement in many disease conditions ranging from cancer to neurodegeneration. To examine the physiological and pathological relevance and functions of FA, fluorescent probes for FA imaging in live biological samples are of great significance. Herein we report a systematic investigation of 2-aza-Cope reactions between homoallylamines and FA for identification of a highly efficient 2-aza-Cope reaction moiety and development of fluorescent probes for imaging FA in living systems. By screening a set of N-substituted homoallylamines and comparing them to previously reported homoallylamine structures for reaction with FA, we found that N-p-methoxybenzyl homoallylamine exhibited an optimal 2-aza-Cope reactivity to FA. Theoretical calculations were then performed to demonstrate that the N-substituent on homoallylamine greatly affects the condensation with FA, which is more likely the rate-determining step. Moreover, the newly identified optimal N-p-methoxybenzyl homoallylamine moiety with a self-immolative ß-elimination linker was generally utilized to construct a series of fluorescent probes with varying excitation/emission wavelengths for sensitive and selective detection of FA in aqueous solutions and live cells. Among these probes, the near-infrared probe FFP706 has been well demonstrated to enable direct fluorescence visualization of steady-state endogenous FA in live mouse brain tissues and elevated FA levels in a mouse model of breast cancer. This study provides the optimal aza-Cope reaction moiety for FA probe development and new chemical tools for fluorescence imaging and biological investigation of FA in living systems.

Size, shape, charge and "stealthy" surface: Carrier properties affect the drug circulation time in vivo.

The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time. For most drugs, sufficient in vivo circulation time is the basis of high bioavailability. Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system, to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect. The physical and chemical properties of drug carriers, such as size, shape, surface charge and surface modification, would affect their in vivo circulation time, metabolic behavior and biodistribution. The final circulation time of carriers is determined by the balance between macrophage recognitions, blood vessel penetration and urine excretion. Therefore, when designing the drug delivery system, we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually. This article mainly reviews the effect of carrier size, size, surface charge and surface properties on its circulation time in vivo, and discusses the mechanism of these properties affecting circulation time. This review has reference significance for the research of long-circulation drug delivery system.