Downregulation of MTHFD2 Inhibits Proliferation and Enhances Chemosensitivity in Hepatocellular Carcinoma via PI3K/AKT Pathway.

BACKGROUND: Despite the substantial impact of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) on cancer progression, its significance in the regulation of hepatocellular carcinoma (HCC) cell proliferation and chemosensitivity remains poorly defined. METHODS: We evaluated MTHFD2 expression in a total of 95 HCC tissues by immunohistochemistry and analyzed the association of MTHFD2 with clinicopathologic features. qRT-PCR and Western blotting were conducted to verify MTHFD2 expression levels. Bioinformatics analysis such as gene set enrichment analysis (GSEA) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were used to predict the signaling pathways involved in MTHFD2. In addition, to investigate the anti-tumor effects of MTHFD2 knockdown, Cell Counting Kit-8 (CCK-8) and EdU assays were used. RESULTS: We found that MTHFD2 was frequently upregulated in HCC, and the combination of increased expression of MTHFD2 and Ki67 was associated with poor HCC prognosis. MTHFD2 knockdown significantly inhibited HCC cell proliferation and effectively sensitized HCC cells to sorafenib and lenvatinib. PI3K/AKT pathway was involved in MTHFD2-mediated modulation of proliferation and chemosensitivity. CONCLUSIONS: These findings indicate that MTHFD2 plays an important role in proliferation and chemosensitivity of HCC, indicating that it may serve as a novel pharmacological target for improving HCC therapy.

A novel axis of circKIF4A-miR-637-STAT3 promotes brain metastasis in triple-negative breast cancer.

Among patients with triple-negative breast cancer (TNBC), distant metastasis is the leading cause of death. Our previous studies have shown that TNBC progression is greatly facilitated by circKIF4A, but uncertainty remains regarding its role in TNBC brain metastasis and the molecular mechanism. In this study, we found notable upregulation of circKIF4A in TNBC cell lines and brain metastases. Inhibition of circKIF4A impaired the ability of TNBC to proliferate, migrate, and cause brain metastasis. Luciferase reporter assays confirmed that circKIF4A competed for binding to miR-637 with STAT3 3' UTR. Western blot analysis revealed that inhibition of circKIF4A decreased STAT3 and p62 expression, while increased the LC3B-II/LC3B-I ratio and the expression of Beclin, indicating that downregulation of circKIF4A induced autophagy by competing with STAT3 for binding to miR-637. By employing a competitive endogenous RNA (ceRNA) mechanism, the circKIF4A-miR-637-STAT3 axis coordinates brain metastasis in TNBC. circKIF4A can therefore be used as a prognostic biomarker for brain metastasis in TNBC and as a therapeutic target.

Graph-Based Restricted and Arbitrary Switching for Switched Positive Systems via a Weak CLCLF.

This article studies the stability problem of discrete-time switched positive linear systems (SPLSs) with marginally stable subsystems. Based on the weak common linear copositive Lyapunov function (weak CLCLF) approach, the switching property and the state component property are combined to ensure the asymptotic stability of SPLSs under three types of switching signals. First, considering the transfer-restricted switching signal described by the switching digraph, novel cycle-dependent joint path conditions are proposed in combination with state component digraphs. Second, under the time interval sequence, two types of path conditions are constructed for designing switching schemes. Third, necessary and sufficient conditions for the asymptotic stability of SPLSs under arbitrary switching are established. Finally, three examples are provided to illustrate the effectiveness of the proposed method.

Recent progress in the oxidative bromination of arenes and heteroarenes.

Oxidative bromination has been serving as a powerful tool for the synthesis of bromo-containing molecules, as this bromination strategy features environmental friendliness, high flexibility in reaction system design and wide abundance of bromide sources and oxidants. The past decade has witnessed a large number of efficient oxidative bromination reaction systems and novel brominated aromatics. This review summarizes recent developments in the field of oxidative preparation of bromoarenes and bromoheteroarenes covering from 2012 to 2022.

Bumpless Transfer Control for Switched Systems via a Dynamic Feedback and a Bump-Dependent Switching Law.

This article investigates the bumpless transfer (BT) control problem of switched systems with unmeasured states. Note that the control input signal of the switched system jumps when switching occurs, which may adversely affect the performance of switched systems. By introducing a modified state observer and an auxiliary continuous control signal, a novel description of the BT performance for the system is presented. Moreover, a compensation-based dynamic BT controller and a bump-dependent switching law are designed to solve the BT control problem. As a result, the developed control method ensures the stability of the closed-loop system while maintaining BT performance. The validation of the results can be provided by applying the proposed BT control method to an example of an aero-engine control system.

Polysaccharide determination and habitat classification for fresh Dendrobiums with hyperspectral imagery and modified RBFNN.

This research aimed to study the visual and nondestructive detection of mannose (MN) and Dendrobium polysaccharides (DP) in Dendrobiums by using hyperspectral imaging technology. In order to determine the MN and DP concentrations nondestructively, we built radial basis function neural network (RBFNN) models based on NIR spectra (874-1734 nm) with a novel chemometric method to calculate the radial bases. And excellent results with the R P 2 coefficients of 0.906 and 0.913 were obtained by the MN and DP detection models, respectively. In order to simplify the detection models based on full-range spectra, we designed an innovative genetic algorithm-successive projections algorithm (GA-SPA) strategy to extract the feature bands efficiently in two stages. Based on the feature bands selected by GA-SPA, we established the simplified detection models with the same high performance as those based on full-range spectra. By importing the feature bands of every pixel in the hyperspectral image into the simplified detection models, we successfully generated the distribution maps of MN and DP. Moreover, we also built an RBFNN classifier to categorize the habitats of Dendrobium. And the total classification accuracy reached 0.887. This research makes progress in Dendrobium quality evaluation and spectral detection technology.

Efficacy and safety of butylphthalide as adjunctive therapy for vascular dementia: A protocol for systematic review and meta-analysis.

BACKGROUND: Butylphthalide is widely used for the adjunctive treatment of vascular dementia; however, the clinical evidences are not well synthesized yet. METHODS: We proposed a systematic review and meta-analysis to evaluate the efficacy and safety of butylphthalide as adjunctive therapy for vascular dementia. Seven electronic databases (China National Knowledge Infrastructure, Wanfang database, Chongqing VIP database, China Biomedical Literature Database, Pubmed, EMBASE and Cochrane library) will be searched for eligible randomized controlled trials (RCTs). Required data of included studies will be collected. Quality of studies will be evaluated using Cochrane risk of bias assessment tool. Data synthesis will be performed using Review Manager software. Subgroup analysis and sensitivity analysis will also be carried. RESULTS: Synthesis results of current available RCTs regarding the efficacy and safety of butylphthalide for the treatment vascular dementia will be provided by this systematic review and meta-analysis. CONCLUSION: This systematic review and meta-analysis will provide high level evidence of butylphthalide clinical application. REGISTRATION: PROSPERO CRD42020168947.

[Preliminary use of HoloLens glasses in surgery of liver cancer].

OBJECTIVE: To establish the preoperative three dimensional (3D) model of liver cancer, and to precisely match the preoperative planning with the target organs during the operation.
 Methods: The 3D model reconstruction based on magnetic resonance data, which was combined with virtual reality technology via HoloLens glasses, was applied in the operation of liver cancer to achieve preoperative 3D modeling and surgical planning, and to directly match it with the operative target organs during operation.
 Results: The 3D model reconstruction of liver cancer based on magnetic resonance data was completed. The exact match with the target organ was performed during the operation via HoloLens glasses leaded by the 3D model.
 Conclusion: Magnetic resonance data can be used for the 3D model reconstruction to improve preoperative assessment and accurate match during the operation.

MicroRNA-138 inhibits cell proliferation in hepatocellular carcinoma by targeting Sirt1.

MicroRNAs (miRNAs) are a family of small, non­coding RNA molecules that are highly conserved across species and function as regulators of gene expression. In the present study, we revealed that miR-138 expression was at a low level while sirtuin type 1 (Sirt1) mRNA expression was at high level in hepatocellular carcinoma tissues and cell lines by using real-time PCR and western blot assays, and the functions of miR-138 were achieved via targeting of Sirt1 using luciferase reporter gene vector and RNA immunoprecipitation assays. Overexpression of miR-138 attenuated Sirt1 expression and inhibited cell proliferation by using CCK-8 and BrdU assays. The inhibitory effect of miR-138 could be partially restored by forced expression of Sirt1 in cells. Our data revealed a crucial role and mechanism of miR-138 in the regulation of hepatocellular carcinoma cell growth via the miR-138/Sirt1 axis, and miR-138 could be an important potential target for the clinical management of hepatocellular carcinoma in the future.

New Three-Component Bicyclization Leading to Densely Functionalized Pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidines.

A novel three-component bicyclization for the efficient synthesis of densely functionalized pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidines has been established from readily accessible aryl aldehydes, α-thiocyanate ketones and pyrazol-5-amines. The reaction pathway involves nucleophilic addition/5-exo-trig /6-endo-trig bicyclization sequence, resulting in continuous multiple bond-forming events including C-N and C-C bonds to rapidly a molecular complexity.

Preparation and in vitro characterization of pluronic-attached polyamidoamine dendrimers for drug delivery.

CONTEXT: Polyamidoamine (PAMAM) dendrimers have attracted lots of interest as drug carriers. And little study about whether pluronic-attached PAMAM dendrimers could be potential drug delivery systems has been carried on. OBJECTIVE: Pluronic F127 (PF127) attached PAMAM dendrimers were designed as novel drug carriers. METHODS: Two conjugation ratios of PF127-attached PAMAM dendrimers were synthesized. (1)H nuclear magnetic resonance ((1)H-NMR), Fourier transform infrared spectrum (FTIR), element analysis and ninhydrin assay were used to characterize the conjugates. Size, zeta potential and critical micelle concentrations (CMC) were also detected. And DOX was incorporated into the hydrophobic interior of the conjugates. Studies on their drug loading and drug release were carried on. Furthermore, hemolysis and cytotoxicity assay were used to evaluate the toxicity of the conjugates. RESULTS AND DISCUSSION: PF127 was successfully conjugated to the fifth generation PAMAM dendrimer at two molar ratios of 19% and 57% (PF127 to surface amine per PAMAM dendrimer molecular). The conjugates showed an increased size and a reduced zeta potential. And higher CMC values were obtained than pure PF127. Compared with unconjugated PAMAM dendrimer, PF127 conjugation significantly reduced the hemolytic toxicity and cytotoxicity of PAMAM dendrimer in vitro. The encapsulation results showed that the ability to encapsulate DOX by the conjugate of 19% conjugation ratio was better than that of 57% conjugation ratio. And the maximum is ∼12.87 DOX molecules per conjugate molecule. Moreover, the complexes showed a sustained release behavior compared to pure DOX. CONCLUSION: Findings from the in vitro study show that the PF127-attached PAMAM dendrimers may be potential carriers for drug delivery.

Microwave-assisted multicomponent reaction in water leading to highly regioselective formation of benzo[f]azulen-1-ones.

Microwave-assisted three-component reaction has been established for the regioselective synthesis of benzo[f]azulen-1-ones. The reaction was performed in aqueous media under microwave irradiation by using readily available and inexpensive starting materials. A total of 38 examples were examined to show a broad substrate scope and good overall yields (70-89%). The present new synthesis shows attractive green chemistry characteristics, such as the use of water as reaction media, concise one-pot conditions, short reaction periods (7-24 min), easy work-up/purification and reduced waste production without the use of any strong acids or metal promoters.

Multicomponent synthesis of poly-substituted benzo[a]pyrano[2,3-c]phenazine derivatives under microwave heating.

A new one-pot two-step tandem synthesis of highly functionalized benzo[a]pyrano[2,3-c]phenazine derivatives via microwave-assisted multicomponent reactions of 2-hydroxynaphthalene-1,4-dione, diamines, aldehydes, and malononitrile is reported. The procedures are facile, avoiding time-consuming and costly syntheses, tedious workup, and purifications of precursors, as well as protection/deprotection of functional groups. The method is expected to find application in the combinatorial synthesis of biologically active compounds, since phenazine and chromene motifs have a broad spectrum of biological activities.

Partitioning and localization of environment-sensitive 2-(2'-pyridyl)- and 2-(2'-pyrimidyl)-indoles in lipid membranes: a joint refinement using fluorescence measurements and molecular dynamics simulations.

Fluorescence of environment-sensitive dyes is widely applied to monitor local structure and solvation dynamics of biomolecules. It has been shown that, in comparison with a parent indole fluorophore, fluorescence of 2-(2'-pyridyl)-5-methylindole (5M-PyIn-0) and 2-[2'-(4',6'-dimethylpyrimidyl)]-indole (DMPmIn-0) is remarkably sensitive to hydrogen bonding with protic partners. Strong fluorescence, observed for these compounds in nonpolar and polar aprotic solvents, is efficiently quenched in aqueous solution. This study demonstrates that 5M-PyIn-0 and DMPmIn-0, which are almost nonemitting in aqueous solution, become highly fluorescent upon titrating with phospholipid vesicles. The fluorescence enhancement is accompanied by a significant blue shift of emission maximum. The Gibbs free energy of membrane partitioning, measured by the increase in the steady-state fluorescence intensities during transfer from an aqueous environment to a lipid bilayer, is very favorable for both compounds, being in a range from -7.1 to -8.0 kcal/mol and depending only slightly on lipid composition of the membrane. The fluorescence enhancement upon membrane partitioning is indicative of the loss of the specific hydrogen-bonding interactions between the excited fluorophore and water molecules, causing efficient fluorescence quenching in bulk water. This conclusion is supported by atomistic molecular dynamics (MD) simulations, demonstrating that both 5M-PyIn-0 and DMPmIn-0 bind rapidly and partition deeply into a lipid bilayer. MD simulations also show a rapid, nanosecond-scale decrease in the probability of solute-solvent hydrogen bonding during passive diffusion of the probe molecules from bulk water into a lipid bilayer. At equilibrium conditions, both 5M-PyIn-0 and DMPmIn-0 prefer deep localization within the hydrophobic, water-free region of the bilayer. A free energy profile of penetration across a bilayer estimated using MD umbrella sampling shows that both indole derivatives favor residence in a rather wide potential energy well located 10-15 Å from the bilayer center.

Design and study of Bi[1,8]naphthyridine ligands as potential photooxidation mediators in Ru(II) polypyridyl aquo complexes.

A series of 3,3'-polymethylene-bridged bi[1,8]naphthyridine (binap) ligands, 3a-c, are complexed with Ru(II) to afford [Ru(tpy)(3a-c)(H(2)O)](2+) where an uncomplexed nitrogen on 3a-c is situated so it can form a H-bond with the coordinated water. An additional complex involving [Ru(4'-NMe(2)tpy)(3b)(H(2)O)](2+) is also prepared. X-ray analyses of the [Ru(tpy)(3a,c)(H(2)O)](2+) complexes indicate well-organized H-bonds even when the binap is nonplanar. In an attempt to realize photooxidation, the effects of light, varying potential, and pH were examined. A Pourbaix diagram indicated that the oxidation potential decreased by approximately 0.5 V in the pH range of 1.9-11.6. The lowest-energy electronic absorption for the binap complexes involves the metal-to-ligand charge transfer to the binap ligand and is sensitive to ligand planarity. The absorbance shifted to a lower energy as the auxiliary ligand became a better donor (4'-NMe(2)tpy) or as the water was deprotonated. Acetonitrile was found to displace water most easily for the complex of 3c, where the ligand is the least planar. Despite promising features, photooxidation of the bound water was not observed.

Ruthenium(II) Complexes of 2-Aryl-1,10-phenanthrolines: Synthesis, Structure, and Photophysical Properties.

The synthesis, characterization, and photochemical investigation of a series of Ru(II) complexes having 2-phenyl- and 2,9-diphenyl substituted phenanthroline ligands are reported. Structural characterization of some of the complexes revealed that the phenyl substituents of the phenanthroline ligand are oriented nearly perpendicular to the phenanthroline ring and pi-stack with adjacent coordinated 2,2'-bipyridyl ligands. Most of the complexes are nonluminescent at room temperature, and temperature-dependent luminescence studies suggest nonradiative relaxation in solution is dominated by rapid thermally activated internal conversion from the initially populated (3)MLCT state to a ligand field (LF) state which decays rapidly to the ground state. The photochemical lability of the complexes was investigated, and it was found that, while the complexes efficiently populate the substitutionally labile LF state, yields for ligand loss are less than expected on the basis of comparison to closely related complexes lacking the phenyl groups which are capable of pi-stacking interactions.