Phosphoglycerate mutase 5 aggravates alcoholic liver disease through disrupting VDAC-1-dependent mitochondrial integrity.

Alcoholic liver disease (ALD) poses a substantial global health challenge, with its pathogenesis deeply rooted in mitochondrial dysfunction. Our study explores the pivotal roles of Phosphoglycerate mutase family member 5 (Pgam5) and Voltage-Dependent Anion Channel 1 (VDAC1) in the progression of ALD, providing novel insights into their interplay and impact on mitochondrial integrity. We demonstrate that Pgam5 silencing preserves hepatocyte viability and attenuates ethanol-induced apoptosis, underscoring its detrimental role in exacerbating hepatocyte dysfunction. Pgam5's influence extends to the regulation of VDAC1 oligomerization, a key process in mitochondrial permeability transition pore (mPTP) opening, mitochondrial swelling, and apoptosis initiation. Notably, the inhibition of VDAC1 oligomerization through Pgam5 silencing or pharmacological intervention (VBIT-12) significantly preserves mitochondrial function, evident in the maintenance of mitochondrial membrane potential and reduced reactive oxygen species (ROS) production. In vivo experiments using hepatocyte-specific Pgam5 knockout (Pgam5hKO) and control mice reveal that Pgam5 deficiency mitigates ethanol-induced liver histopathology, inflammation, lipid peroxidation, and metabolic disorder, further supporting its role in ALD progression. Our findings highlight the critical involvement of Pgam5 and VDAC1 in mitochondrial dysfunction in ALD, suggesting potential therapeutic targets. While promising, these findings necessitate further research, including human studies, to validate their clinical applicability and explore broader implications in liver diseases. Overall, our study provides a significant advancement in understanding ALD pathophysiology, paving the way for novel therapeutic strategies targeting mitochondrial pathways in ALD.

Surface Gradient Desodiation Chemistry in Layered Oxide Cathode Materials.

Sodium-ion batteries (SIBs) as a promising technology for large-scale energy storage have received unprecedented attention. However, the cathodes in SIBs generally suffer from detrimental cathode-electrolyte interfacial side reactions and structural degradation during cycling, which leads to severe capacity fade and voltage decay. Here, we have developed an ultra-stable Na0.72Ni0.20Co0.21Mn0.55Mg0.036O2 (NCM-CS-GMg) cathode material in which a Mg-free core is encapsulated by a shell with gradient distribution of Mg using coprecipitation method with Mg-hysteretic cascade feedstock followed by calcination. From the interior to outer surface of the shell, as the content of electrochemically inactive Mg gradually increases, the Na+ deintercalation amount gradually decreases after charged. Benefiting from this surface gradient desodiation, the surface transition metal (TM) ion migration from TM layers to Na layers is effectively inhibited, thus suppressing the layered-to-rock-salt phase transition and the resultant microcracks. Besides, the less formation of high-valence TM ions on the surface contributes to a stable cathode-electrolyte interface. The as-prepared NCM-CS-GMg exhibits remarkable cycling life over 3000 cycles with a negligible voltage drop (0.127 mV per cycle). Our findings highlight an effective way to developing sustainable cathode materials without compromising on the initial specific capacity for SIBs.

Effect of Ultrasonic Treatment on Structure, Antibacterial Activity of Sugarcane Leaf Polysaccharides.

This study investigated the impact of ultrasonic extraction (UE) on the structure and in vitro antibacterial activity of polysaccharides from sugarcane leaves (SLW). Native sugarcane leaf polysaccharides were treated with ultrasound (480 W) for 3 h to yield sugarcane leaf polysaccharides (SLU). Compared to SLW (33.59 kDa), the molecular weight of SLU (13.08 kDa) was significantly decreased, while the monosaccharide composition of SLU was unchanged. The results of SEM and XRD indicated that UE significantly changed the surface morphology of SLW and destroyed its inner crystalline structure. In vitro experiments showed that SLU had stronger antibacterial activity. These findings revealed that UE treatment could alter the tertiary structure of SLW but had no impact on its primary structure. Furthermore, the antibacterial activity of SLW could be greatly enhanced after UE treatment. As a bioactive additive, SLU has great application potential in functional foods, cosmetics, and pharmaceuticals.

Vanadium dioxide-assisted broadband absorption and linear-to-circular polarization conversion based on a single metasurface design for the terahertz wave.

Integrating tunable characteristics and multiple functions into a single metasurface has become a new scientific and technological undertaking that needs to deal with huge challenges, especially in the terahertz frequency region. The multifunctional design combining the broadband absorption and broadband polarization conversion using a single switchable metasurface is proposed in this paper. The switchable performance can be realized by treating the insulation to metal phase transition properties of vanadium dioxide (VO2). At high temperature (74 °C), the proposed metasurface can be used as a broadband absorber which consists of a VO2 square ring, polyimide (PI) spacer, and VO2 film. Simulated results show that the terahertz wave absorption can reach above 90% with the bandwidth ratio of 75% in the frequency range of 0.74 THz-1.62 THz. This absorber is insensitive to polarization resulted from the symmetry structure and also shows a good performance at large incident angles. Once the temperature is lower than the cooling phase transition temperature (about 62 °C) and VO2 is in insulation state, the metasurface can be transformed into a broadband linear-to-circular polarization converter. Numerical simulation depicts that the ellipticity reaches to -1 and the axis ratio is lower than 3 dB from 1.47 THz to 2.27 THz. The designed switchable metasurface provides the potential to be used in the fields of advanced research and intelligent applications in the terahertz frequency region.

Electronic Coupling and Electron Transfer between Two Mo2 Units through meta- and para-Phenylene Bridges.

A series of three Mo2 dimers bridged by a meta-phenylene group has been studied in terms of electronic coupling (EC) and electron transfer (ET) in comparison with the para isomers. Optical analyses on the mixed-valence complexes indicate that by replacing a para-phenylene bridge with a meta one, the EC between the two Mo2 centers is dramatically weakened; consequently, the ET rates (ket ) are lowered by two to three orders of magnitude. In the para series, the EC parameters (Hab ) and ET rates (ket ) are greatly affected by O/S atomic alternation of the bridging ligand. However, for the meta analogues, similar EC and ET parameters are obtained, that is, Hab =300-400 cm-1 and ket ≈109  s-1 . These results suggest that through-σ-bond and/or through-space coupling channels become operative as the π conjugation is disabled. DFT calculations reveal that destructive quantum interference features seen for the meta series arise from the cancellation of two π-conjugated coupling pathways.

Mapping Bridge Conformational Effects on Electronic Coupling in Mo2-Mo2 Mixed-Valence Systems.

The large bridging ligand 9,10-anthracenedicarboxylate and its thiolated derivatives have been employed to assemble two dimolybdenum complex units and develop three Mo2 dimers, [Mo2(DAniF)3]2(µ-9,10-O2CC14H8CO2), [Mo2(DAniF)3]2(µ-9,10-OSCC14H8COS), and [Mo2(DAniF)3]2(µ-9,10-S2CC14H8CS2) (DAniF = N, N'-di( p-anisyl)formamidinate), for the study of conformation dependence of the electronic coupling between the two Mo2 centers. These compounds feature a large deviation of the central anthracene ring from the plane defined by the Mo-Mo bond vectors, with the torsion angles (ϕ = 50-76°) increasing as the chelating atoms of the bridging ligand vary from O to S. Consequently, the corresponding mixed-valence complexes do not exhibit characteristic intervalence charge transfer absorptions in the near-IR spectra, in contrast to the phenylene and naphthalene analogues, from which these systems are assigned to the Class I in Robin-Day's scheme. Together with the phenylene and naphthalene series, the nine total mixed-valence complexes in three series complete a transition from the electronically uncoupled Class I to the strongly coupled Class II-III borderline via moderately coupled Class II and permit a systematic mapping of the bridge conformation effects on electronic coupling. Density functional theory calculations show that the HOMO-LUMO energy gap, corresponding to the metal (δ) to ligand (π*) transition energy, and the magnitude of HOMO-HOMO-1 splitting in energy are linearly related to cos2 ϕ. Therefore, our experimental and theoretical results concur to indicate that the coupling strength decreases in the order of the bridging units: phenylene > naphthalene > anthracene, which verifies the through-bond superexchange mechanism for electronic coupling and electron transfer.

A Comprehensive Comparative Study on Inductive and Ultrasonic Wireless Power Transmission to Biomedical Implants.

This paper presents a comprehensive comparison between inductive coupling and ultrasound for wireless power transmission (WPT) to biomedical implants. Several sets of inductive and ultrasonic links for different powering distances (d 12) and receiver dimensions have been optimized, and their key parameters, including power transmission efficiency (PTE) and power delivered to the load (PDL) within safety constraints, have been compared to find out which method is optimal for any given condition. Two design procedures have been presented for maximizing the PTE of inductive and ultrasonic links by finding the optimal geometry for the transmitter (Tx) and receiver (Rx) coils and ultrasonic transducers as well as the optimal operation frequency (fp ). Our simulation and measurement results showed that the ultrasonic link transcends the inductive link in PTE and somewhat in PDL for a small Rx of 1.1 mm3 (diameter of 1.2 mm), particularly when the Rx was deeply implanted inside the tissue (d 12 ≥ 10 mm). However, for a larger 20 mm3 Rx (diameter of 5 mm), the inductive link achieved higher PTE and PDL, particularly at shorter distances (d 12 < 30 mm). The optimal loading condition is shown to be quite different in inductive and ultrasonic links. Despite higher performance for small Rx and large d 12, the ultrasonic link is more sensitive to Rx misalignments and orientations. This led us to propose a new design procedure based on the worst-case misalignment scenario. The simulation results have been validated by measurements. The inductive and ultrasonic links, operating at 30 MHz and 1.1 MHz, achieved measured PTEs of 0.05% and 0.65% for the 1.1 mm3 Rx located 30 mm inside tissue and oil environments with optimal load resistances of 295 Ω and 3.8 kΩ, respectively.

Typing of chronic obstructive pulmonary disease using high-resolution computed tomography and the association with smoking, airway inflammation, and common comorbidities

Background/aim: This study performed typing of chronic obstructive pulmonary disease (COPD) using high-resolution computed tomography (HRCT) to determine the association with smoking, matrix metalloproteinases, and common comorbidities. Materials and methods: The study enrolled 94 hospitalized patients. Participants were divided into a group of 69 current and former smokers (group A) and a group of 25 that had never smoked (group B). Patients were also divided into 3 categories according to the degree of emphysema and bronchial wall thickness using HRCT to determine the association with levels of matrix metalloproteinase 9 (MMP-9) and TIMP-1, as well as associated comorbidities. These three categories were: type A - no or mild emphysema, with or without bronchial wall thickening; type E - emphysema without bronchial wall thickening; and type M - both emphysema and bronchial wall thickening. Results: The low attenuation area (LAA) scores in group A patients were higher than those in group B (t = 2.86, P < 0.01); correlation analysis showed that smoking was associated with a decline of the forced expiratory volume in 1 s and forced vital capacity ratio (FEV1/ FVC%) and higher LAA scores in patients with COPD (F = 4.46, F = 8.20, P < 0.05). The levels of MMP-9 in group A were higher than those in group B (t = 3.65, P < 0.01). Among COPD patients with more than 3 comorbidities, there were statistically significant differences in both the smoking group and the nonsmoking group (chi-square = 12.08, P < 0.01). When compared to type A patients, who had coincident cardiovascular diseases in the smoking group, patients of type M and E showed statistically significant differences (F = 2.42 and 2.12, P < 0.05). Conclusion: Emphysema was more severe in smokers. Metalloproteinase levels in smokers were higher than those in nonsmokers. Moreover, comorbidities were more severe in smokers.

The role of regulatory B cells in digestive system diseases.

INTRODUCTION: The past decade has provided striking insights into a newly identified subset of B cells known as regulatory B cells (Bregs). In addition to producing antibody, Bregs also regulate diseases via cytokine production and antigen presentation. This subset of B cells has protective and potentially therapeutic effects. However, the particularity of Bregs has caused some difficulties in conducting research on their roles. Notably, human B10 cells, which are Bregs that produce interleukin 10, share phenotypic characteristics with other previously defined B cell subsets, and currently, there is no known surface phenotype that is unique to B10 cells. METHODS: An online search was performed in the PubMed and Web of Science databases for articles published providing evidences on the role of regulatory B cells in digestive system diseases. RESULTS AND CONCLUSIONS: Abundant evidence has demonstrated that Bregs play a regulatory role in inflammatory, autoimmune, and tumor diseases, and regulatory B cells play different roles in different diseases, but future work needs to determine the mechanisms by which Bregs are activated and how these cells affect their target cells.

Charge Transfer Properties of Triarylamine Integrated Dimolybdenum Dyads.

Three quadruply bonded dimolybdenum complexes equipped with a triarylamine pendant, [(DAniF)3Mo2(µ-O2CC6H4N(C6H4CH3)2] (DAniF = N,N'-di(p-anisyl)formamidinate; [OO-ph-N]), [(DAniF)3Mo2(µ-OSCC6H4N(C6H4CH3)2] ([OS-ph-N]), and [(DAniF)3Mo2(µ-S2CC6H4N(C6H4CH3)2] ([SS-ph-N]), have been synthesized and characterized by single crystal X-ray diffraction. In electrochemical measurements, the redox couple for the organic amine group becomes irreversible, reflecting the substantially strong electronic interaction between the dimetal center and organic redox site. The potential difference for the two successive redox events, ca. ΔE1/2(E1/2(2)(N/N•+) - E1/2(1)(Mo2IV/V)), falls in the range of 0.5-0.8 V as estimated from the differential pulse voltammograms. For the monocation radicals [OO-ph-N]+, [OS-ph-N]+, and [SS-ph-N]+, obtained by chemical oxidation of the neutral precursor, a broad ligand (amine) to metal (Mo2) charge transfer (LMCT) absorption band is observed in the near-IR region. Interestingly, analogous to the intervalence charge transfer (IVCT) bands for mixed-valence complexes, the LMCT absorption bands, which are solvent dependent, decrease in energy and bandwidth as the electronic coupling between the two redox sites increases in an order of increasing S content in the chelating group. The electronic coupling matrix elements (Hab) are determined by optical analyses from the generalized Mulliken-Hush (GMH) theory, falling in the range of 400-800 cm-1 in CH2Cl2. These results indicate that in these radical cations the charge is localized. Time-dependent DFT calculations show that the frontier molecular orbitals for these asymmetrical donor-acceptor systems have unbalanced distribution of electron density, and the LMCT bands arise from an electronic transition from the pendant ligand-based to metal-based molecular orbitals, corresponding to donor (N)-acceptor (Mo2) charge transfer.

Aromaticity-Driven Molecular Structural Variation and Electronic Configuration Alternation: An Example of Cyclic π Conjugation Involving a Mo-Mo δ Bond.

We have synthesized and characterized the mixed-ligand dimolybdenum paddlewheel complex Na[(DAniF)3Mo2(C3S5)] (Na[1]; DAniF = N,N'-di-p-anisylformamidinate, dmit = 1,3-dithiole-2-thione-4,5-dithiolate), which has a six-membered chelating [Mo2S2C2] ring created by equatorial coordination of the dmit (C3S5) ligand to the Mo2 unit. One-electron oxidation of Na[1] using Cp2FePF6 yields the neutral complex [(DAniF)3Mo2(C3S5)] ([1]), and removal of two electrons from Na[1] using AgBPh4 gives [(DAniF)3Mo2(C3S5)]BPh4 ([1]BPh4). In the crystal structures, [1]- and [1] present dihedral angles of 118.9 and 142.3° between the plane defined by the Mo-Mo bond vector and the dmit ligand, respectively, while DFT calculations show that in [1]+ the Mo-Mo bond and the dmit ligand are coplanar. Complex [1] is paramagnetic with a g value of 1.961 in the EPR spectrum and has a Mo-Mo bond distance of 2.133(1) Å, increased from 2.0963(9) Å for [1]-. Consistently, a broad absorption band is observed for [1] in the near-IR region, which arises from charge transfer from the dmit ligand to the cationic Mo25+ centers. Interestingly, complex [1]+ has an aromatic [Mo2S2C2] core, as evidenced by a large diamagnetic anisotropy, in addition to the coplanarity of the core structure, which shifts downfield the 1H NMR signal of the horizontal methine proton (ArN-(CH)-NAr) but upfield those of the vertical protons, relative to the methine proton resonances for the precursor ([1]-). The magnetic anisotropy (Δχ = χ⊥ - χ∥) for the [Mo2S2C2] ring in [1]+ is -105.5 ppm cgs, calculated from the McConnell equation, which is about 2-fold larger than that for benzene. The aromaticity of the [Mo2S2C2] ring is supported by theoretical studies, including single-point calculations and gauge-including atomic orbital (GIAO) NMR spectroscopic calculations at the density functional theory (DFT) level. DFT calculations also show that the [Mo2S2C2] core in [1]+ possesses a set of three highest occupied and three lowest unoccupied molecular orbitals in π character, corresponding to those of benzene in symmetry, and six π electrons that conform to the Hückel 4n + 2 rule for aromaticity. Therefore, this study shows that an aromatic [Mo2S2C2] core is formed by coupling the δ orbital of the Mo≣Mo bond with the π orbital of the C═C bond through the bridging atoms (S), thus validating the equivalency in bonding functionality between δ and π orbitals.

Photoinduced δ electron transfer in phenylene bridged Mo2 dimers.

Photoinduced electron transfer (ET) in Mo2 dimers, [Mo2(DAniF)3]2(µ-E2C(ph)CE2) (DAniF = N,N'-di(p-anisyl)formamidinate, E = O or S), has been studied by femtosecond transient spectral techniques. Using a 355 nm laser pulse, the δ electrons on the Mo-Mo quadruple bonds are selectively excited and subsequent charge separation yields diradicals [Mo2]˙--ph-[Mo2]˙+ and [Mo2]-ph˙--[Mo2]˙+. The charge separation (CS) and recombination (CR) rates are derived by fitting the decay kinetic data of the excited states. Surprisingly, it is found that the CR rate constants (kCR-1, ∼1012 s-1) for [Mo2]˙--ph-[Mo2]˙+ are larger than the data (kCR-2) for [Mo2]-ph˙--[Mo2]˙+ by about one order of magnitude, although in the first case, the ET distance is doubled and the electronic coupling between the donor and acceptor is weaker. Optical analyses reveal that the free energy changes (ΔG°) for the two CR processes correspond to the δ → δ* and the metal (δ) to bridging ligand (π*) transition energies, respectively, and thus, the ET kinetics is dominated likely by the driving force (-ΔG°).

Tuning the Electronic Coupling and Electron Transfer in Mo2 Donor-Acceptor Systems by Variation of the Bridge Conformation.

Assembling two quadruply bonded dimolybdenum units [Mo2 (DAniF)3 ](+) (DAniF=N,N'-di(p-anisyl)formamidinate) with 1,4-naphthalenedicarboxylate and its thiolated derivatives produced three complexes [{Mo2 (DAniF)3 }2 (µ-1,4-O2 CC10 H6 CO2 )], [{Mo2 (DAniF)3 }2 (µ-1,4-OSCC10 H6 COS)], and [{Mo2 (DAniF)3 }2 (µ-1,4-S2 CC10 H6 CS2 )]. In the X-ray structures, the naphthalene bridge deviates from the plane defined by the two Mo-Mo bond vectors with the torsion angle increasing as the chelating atoms of the bridging ligand vary from O to S. The mixed-valent species exhibit intervalence transition absorption bands with high energy and very low intensity. In comparison with the data for the phenylene analogues, the optically determined electronic coupling matrix elements (Hab =258-345 cm(-1) ) are lowered by a factor of two or more, and the electron-transfer rate constants (ket ≈10(11)  s(-1) ) are reduced by about one order of magnitude. These results show that, when the electron-transporting ability of the bridge and electron-donating (electron-accepting) ability of the donor (acceptor) are both variable, the former plays a dominant role in controlling the intramolecular electron transfer. DFT calculations revealed that increasing the torsion angle enlarges the HOMO-LUMO energy gap by elevating the (bridging) ligand-based LUMO energy. Therefore, our experimental results and theoretical analyses verify the superexchange mechanism for electronic coupling and electron transfer.

Electronic Coupling between Two Covalently Bonded Dimolybdenum Units Bridged by a Naphthalene Group.

Using 2,6-naphthalenedicarboxylate and its thiolated derivatives as bridging ligands, three Mo2 dimers of the type [Mo2(DAniF)3](E2CC10H6CE2)[Mo2(DAniF)3] (DAniF = N,N'-di-p-anisylformamidinate; E = O, S) have been synthesized and characterized by X-ray diffraction. These compounds can be generally formulated as [Mo2]-naph-[Mo2], where the complex unit [Mo2] ([Mo2(DAniF)3(µ-E2C)]) functions as an electron donor (acceptor) and the naphthalene (naph) group is the bridge. The mixed-valence (MV) complexes, generated by one-electron oxidation of the neutral precursors, display weak, very broad intervalence charge-transfer absorption bands in the near-to-mid-IR regions. The electronic coupling matrix elements for the MV complexes, Hab = 390-570 cm(-1), are calculated from the Mulliken-Hush equation, which fall between those for the phenyl (ph) and biphenyl (biph) analogues reported previously. The three series consisting of three complexes with the same [Mo2] units exhibit exponential decay of Hab as the bridge changes from ph to biph via naph, with decay factors of 0.21-0.17 Å(-1). Therefore, it is evidenced that while the extent of the bridge conjugacy varies, the electronic coupling between the two [Mo2] units is dominated by the Mo2···Mo2 separation. The absorption band energies for metal-to-ligand charge transfer are in the middle of those for the ph and biph analogues, which is consistent with variation of the HOMO-LUMO energy gaps for the complex series. These results indicate that the interplay of the bridge length and conjugacy is to affect the enegy for charge transfer crossing the intervening moiety, in accordance with a superechange mechanism.

Distinguishing the strength of electronic coupling for Mo2 -containing mixed-valence compounds within the Class III regime.

Two, symmetrical, mixed-valence (MV), complex cations-{[Mo2 (DAniF)3 ]2 (µ-oxamidate)}(+) (1(+) ) and {Mo2 (DAniF)3 ]2 (µ-dithiooxamidate)}(+) (2(+) ; DAniF=N,N'-di(p-anisyl)formamidinate)-are significantly differentiated in terms of electronic coupling between the two [Mo2 ] units. For 1(+) the intervalence (IV) charge-transfer band in the near-IR spectrum is truncated in half on the low-energy side as predicted for MV compounds at the Class II-III limit (2Hab /λ=1; for which Hab =electronic coupling matrix element and λ=reorganization energy). In contrast, the very strongly coupled analogue 2(+) , as indicated by 2Hab /λ=3.5 (> >1), exhibits a higher energy and more symmetrical IV band. As rare examples, this pair of MV species shows distinct optical behaviors for MV systems crossing the Class III region. Optical analysis and DFT calculations are carried out to elucidate the transformation from vibronic to electronic vertical transition.

Electronic Coupling in [Mo2]-Bridge-[Mo2] Systems with Twisted Bridges.

In order to evaluate the impact of bridge conformation on electronic coupling in donor-bridge-acceptor triad systems, two Mo2 dimers, [Mo2(DAniF)3]2[µ-1,4-{C(O)NH}2-Naph] (1, DAniF = N,N'-di(p-anisyl)formamidinate and Naph = naphthalenyl) and [Mo2(DAniF)3]2[µ-1,4-(CS2)2-2,5-Me2C6H2] (2), have been synthesized and structurally characterized. These two compounds feature a large dihedral angle (>60°) between the central aromatic ring and the plane defined by the Mo-Mo bond vectors, which is distinct from the previously reported phenylene bridged analogues [Mo2(DAniF)3]2[µ-1,4-{C(O)NH}2-ph] (I) and [Mo2(DAniF)3]2[µ-1,4-(CS2)2-C6H4] (II), respectively. Unusual optical behaviors are observed for the mixed-valence (MV) species (1(+) and 2(+)), generated by single-electron oxidation. While 2(+) exhibits a weak intervalence charge transfer (IVCT) absorption band in the near-IR region, the IVCT band is absent in the spectrum of 1(+), which is quite different from what observed for I(+) and II(+). Optical analyses, based on superexchange formalism and Hush model, indicate that, in terms of Robin-Day classification, mixed-valence species 1(+) belongs to the electronically uncoupled Class I and complex 2(+), with Hab = 220 cm(-1), is assigned to the weakly coupled Class II. Together with I(+) and II(+), the four MV complexes complete a transition from Class I to Class II-III borderline as a result of manipulating the geometric topology of the bridge. Given the structural and electronic features for the molecular systems, the impacts of electrostatic interaction (through-space) and electron resonance (through-bond) on electronic coupling are discussed.

Perturbation of the charge density between two bridged Mo2 centers: the remote substituent effects.

A series of terephthalate-bridged dimolybdenum dimers with various formamidinate ancillary ligands, denoted as [Mo2(ArNCHNAr)3]2(µ-O2CC6H4CO2) (Ar = p-XC6H4, with X = OCH3 (1), CH3 (2), F (3), Cl (4), OCF3 (5), and CF3 (6)), has been synthesized and studied in terms of substituent effects on electron delocalization between the two dimetal sites. X-ray structural analyses show that these complexes share the same molecular scaffold with the para-substituents (X) being about 8 Å away from the Mo2 center. It is found that the remote substituents have the capability to tune the electronic properties of the complexes. For the series 1 to 6, the metal-metal bond distances (d(Mo-Mo)) decrease slightly and continuously; the potential separations (ΔE(1/2)) for the two successive one-electron oxidations decrease constantly, and the metal to ligand transition energies (λ(max)) increase in order. More interestingly, the two types of methine protons, H(∥) on the horizontal and H(⊥) on the vertical ligands with respect to the plane defined by the Mo-Mo bond vectors and bridging ligand, display separate resonant signals δ(∥) and δ(⊥) in the NMR spectra. The displacements of the chemical shifts, Δδ(∥-⊥) = δ(∥) - δ(⊥), are getting smaller as the substituents vary from electron-donating to -withdrawing. These results show that the peripheral groups on the [Mo2] units function to fine-tune the metal-metal interactions crossing the bridging ligand. The experimental parameters, ΔE(1/2), λ(max), and Δδ(∥-⊥), which are linearly related with the Hammett constants (σ(X)) of the X groups, can be used to probe the charge density on the two [Mo2] units and the electronic delocalization between them.

Efficacy and safety of Argatroban in patients with acute ischemic stroke: a systematic review and meta-analysis.

Objective: Argatroban is a highly promising drug for the treatment of acute ischemic stroke (AIS), but there is currently insufficient strong evidence regarding the efficacy and safety of using Argatroban in the treatment of AIS. Therefore, we conducted a systematic review and meta-analysis to evaluate the effectiveness and safety of Argatroban in the treatment of AIS. Methods: Articles on PubMed, Embase and the Cochrane Library databases were searched from these websites' inceptions to 2th February 2023. Randomized controlled trials and observational studies on Argatroban therapy for acute ischemic stroke were included. Meta-analyses were conducted using a random-effects model. Results: Fourteen studies involving 10,315 patients were included in the meta-analysis. The results showed a significant reduction in the rate of early neurological deterioration (END) in the Argatroban group compared with the control group (OR = 0.47, 95% CI: 0.31-0.73, I2 = 15.17%). The rates of adverse events were no significant difference between the two groups (ICH: OR = 1.02, 95% CI: 0.68-1.51, I2 = 0.00%; major extracranial bleeding: OR = 1.22, 95% CI: 1.01-1.48, I2 = 0.00%; mortality: OR = 1.16, 95% CI: 0.84-1.59, I2 = 0.00%). However, the rates of mRS score of 0-1 (OR = 1.38, 95% CI: 0.71-2.67, I2 = 77.56%) and mRS score of 0-2 (OR = 1.18, 95% CI: 0.98-1.42, I2 = 0.00%) during the 90 days did not significantly improved in the Argatroban group. Subgroup analyses showed that the rate of END (OR = 0.41, 95% CI: 0.26-0.65, I2 = 2.77%) and mRS score of 0-2 (OR = 1.38, 95% CI: 1.06-1.81, I2 = 0.00%) had significantly improved when the intervention group adopted Argatroban plus Antiplatelet. Conclusion: Argatroban can improve neurological deterioration, with a low incidence of adverse events such as bleeding and death, and general analysis showed no improvement in mRS. However, subgroup analysis suggests that compared to mono-antiplatelet therapy, combination therapy of Argatroban combined with antiplatelet therapy significantly reduced the incidence of END and improved mRS scores. After using Argatroban, there was no increase in the risk and mortality of intracranial hemorrhage and other bleeding sites.

Arsenic trioxide augments immunogenic cell death and induces cGAS-STING-IFN pathway activation in hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and immunotherapy. Arsenic trioxide (ATO) has emerged as a cytotoxic agent effective for treating solid tumors, including advanced HCC. However, its effectiveness in HCC treatment remains limited, and the underlying mechanisms are still uncertain. Therefore, this study aimed to characterize the effects and mechanisms of ATO in HCC. By evaluating the susceptibilities of human and murine HCC cell lines to ATO treatment, we discovered that HCC cells exhibited a range of sensitivity to ATO treatment, highlighting their inherent heterogeneity. A gene signature comprising 265 genes was identified to distinguish ATO-sensitive from ATO-insensitive cells. According to this signature, HCC patients have also been classified and exhibited differential features of ATO response. Our results showed that ATO treatment induced reactive oxygen species (ROS) accumulation and the activation of multiple cell death modalities, including necroptosis and ferroptosis, in ATO-sensitive HCC cells. Meanwhile, elevated tumoral immunogenicity was also observed in ATO-sensitive HCC cells. Similar effects were not observed in ATO-insensitive cells. We reported that ATO treatment induced mitochondrial injury and mtDNA release into the cytoplasm in ATO-sensitive HCC tumors. This subsequently activated the cGAS-STING-IFN axis, facilitating CD8+ T cell infiltration and activation. However, we found that the IFN pathway also induced tumoral PD-L1 expression, potentially antagonizing ATO-mediated immune attack. Additional anti-PD1 therapy promoted the anti-tumor response of ATO in ATO-sensitive HCC tumors. In summary, our data indicate that heterogeneous ATO responses exist in HCC tumors, and ATO treatment significantly induces immunogenic cell death (ICD) and activates the tumor-derived mtDNA-STING-IFN axis. These findings may offer a new perspective on the clinical treatment of HCC and warrant further study.

miR-196a overexpression and miR-196a2 gene polymorphism are prognostic predictors of oral carcinomas.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is prevalent worldwide, and survival in OSCC has not improved significantly in the last few decades. MicroRNAs have an important regulatory role in oral carcinogenesis. This study investigated the prognostic implications of miR-196 expression and the rs11614913 genotype of the miR-196a2 gene in OSCC. METHODS: The clinicopathologic implications of miR-196 in OSCC were investigated using expression assays and genotyping, and the functional role of miR-196 in OSCC pathogenesis was investigated using exogenous expression and knockdown. RESULTS: miR-196 was up-regulated in OSCC tissue relative to control mucosa. High expression of miR-196a, but not miR-196b, was associated with tumor recurrence, nodal metastasis, and mortality. Plasma miR-196a levels could be used to distinguish patients from controls with a separating power of 0.75. Multivariate analysis showed that both high miR-196a expression and TT genotype were independent predictors for poor survival in OSCC. The risk of mortality was greatest for patients with high miR-196a level and positive node status. Expression of miR-196 enhanced oncogenesis of OSCC cells, while inhibition of miR-196 expression attenuated such effects. CONCLUSIONS: High miR-196a expression in tumor tissue and the presence of the TT variant of miR-196a2 gene indicate worse survival in OSCC.