Unlocking a new hydrogen-bonding marker: C-O bond shortening in vicinal diols revealed by rotational spectroscopy.

The conformational space of cis-1,2-cyclohexanediol, a model molecule for cyclic vicinal diols, was investigated using rotational spectroscopy and density functional theory calculations. Four low energy conformers within an energy window of 5 kJ mol-1 were identified computationally. A rotational spectrum of jet-cooled cis-1,2-cyclohexanediol was recorded with a chirped pulse Fourier transform microwave spectrometer. Two sets of rotational transitions were observed and could be assigned to conformers of cis-1,2-cyclohexanediol. The non-observation of other low energy conformers was explained by conformational conversion barrier height calculations and results from experimental spectra recorded with different carrier gases. Eight isotopologues, including those with 13C and 18O, of the lowest energy conformer were observed, allowing the determination of the semi-experimental equilibrium structure, reSE. Interestingly, the structural analysis revealed that the C-O bond length of the intramolecular hydrogen-bond donor is shorter than that of the acceptor. This appears to be a general characteristic of vicinal diols and can be used as a novel hydrogen-bond marker in such compounds.

Drug-Loaded Tumor-Derived Microparticles Elicit CD8+ T Cell-Mediated Anti-Tumor Response in Hepatocellular Carcinoma.

Background: Hepatocellular Carcinoma (HCC) poses significant challenges due to limited effective treatments and high recurrence rates. Immunotherapy, a promising approach, faces obstacles in HCC patients due to T-cell exhaustion and immunosuppression within the tumor microenvironment. Methods: Using doxorubicin-loaded tumor-derived microparticles (Dox-TMPs), the mice with H22 ascites model and subcutaneous tumors model were treated. Following the treatment, mice were re-challenged with H22 cells to compare the therapeutic effects and recurrence among different groups of mice, alongside examining the changes in the proportions of immune cells within the tumor microenvironment. Furthermore, Dox-TMPs were combined with anti-PD-1 to further validate their anti-tumor efficacy. In vitro studies using various liver cancer cell lines were conducted to verify the tumor-killing effects of Dox-TMPs. Additionally, CD8+ T cells from the abdominal cavity of tumor-free mice were co-cultured with H22 cells to confirm their specific tumor-killing abilities. Results: Dox-TMPs demonstrate effective anti-tumor effects both in vitro and in vivo. In vivo, their effectiveness primarily involves enhancing CD8+ T cell infiltration, alleviating T cell immunosuppression, and improving the immune microenvironment to combat tumors. When used in combination with anti-PD-1, their anti-tumor effects are further enhanced. Moreover, some mice treated with Dox-TMPs developed anti-tumor immunity, displaying a self-specific T-cell immune response upon re-challenged with tumor cells. This suggests that Dox-TMPs also have the potential to act as a long-term immune response against tumor recurrence, indicating their capability as a tumor vaccine. Conclusion: Dox-TMPs exhibit a dual role in liver cancer by regulating T cells within the tumor microenvironment, functioning both as an anti-tumor agent and a potential tumor vaccine.

Binary conformers of a flexible, long-chain fluoroalcohol: dispersion controlled selectivity and relative abundances in a jet.

The complex conformational panorama of binary 4,4,4-trifluoro-1-butanol (TFB) aggregates was investigated using chirped-pulse Fourier transform microwave spectroscopy, aided by conformational searches using CREST (Conformer-Rotamer Ensemble Sampling Tool) and quantum chemistry calculations. From nearly 1500 initial dimer geometries, 16 most stable binary candidates were obtained within a relative energy window of ∼4 kJ mol-1. Rotational spectra of five binary conformers were experimentally observed in supersonic expansion and assigned. Interestingly, three out of the five observed binary conformers are composed solely of monomer conformers, which were not observed in their isolated gas phase forms in jet expansion. In addition, an observed dimer that is made exclusively of the most stable TFB monomer subunits does not correspond to the global minimum. The intricate kinetically and thermodynamically controlled dimer formation mechanisms are discussed, and a modified kinetic-thermodynamic model was developed, providing conformational abundances that are in good agreement with the experiment. Subsequent non-covalent interaction analyses reveal that the observed conformers are held together by one primary O-H⋯O hydrogen bond and secondary intermolecular C-H⋯O, C-H⋯F, and/or O-H⋯F interactions, as well as C-H⋯H-C London dispersion interactions between the methylene groups. Further symmetry-adapted perturbation theory analyses of the TFB dimer conformers and related alcohol dimers reveal a considerable rise in dispersion contributions with increasing n-alkyl carbon chain length and highlight the role of dispersion interactions in preferentially stabilizing the global minimum of the TFB dimer.

Lutetium texaphyrin: A photocatalyst that triggers pyroptosis via biomolecular photoredox catalysis.

Photon-controlled pyroptosis activation (PhotoPyro) is a promising technique for cancer immunotherapy due to its noninvasive nature, precise control, and ease of operation. Here, we report that biomolecular photoredox catalysis in cells might be an important mechanism underlying PhotoPyro. Our findings reveal that the photocatalyst lutetium texaphyrin (MLu) facilitates rapid and direct photoredox oxidation of nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, and various amino acids, thereby triggering pyroptosis through the caspase 3/GSDME pathway. This mechanism is distinct from the well-established role of MLu as a photodynamic therapy sensitizer in cells. Two analogs of MLu, bearing different coordinated central metal cations, were also explored as controls. The first control, gadolinium texaphyrin (MGd), is a weak photocatalyst but generates reactive oxygen species (ROS) efficiently. The second control, manganese texaphyrin (MMn), is ineffective as both a photocatalyst and a ROS generator. Neither MGd nor MMn was found to trigger pyroptosis under the conditions where MLu was active. Even in the presence of a ROS scavenger, treating MDA-MB-231 cells with MLu at concentrations as low as 50 nM still allows for pyroptosis photo-activation. The present findings highlight how biomolecular photoredox catalysis could contribute to pyroptosis activation by mechanisms largely independent of ROS.

The relationship between albumin corrected anion gap levels and mortality in patients with asthma in the ICU.

Although previous studies have suggested that albumin-corrected anion gap (ACAG) may be a predictor of mortality in critically ill patients in intensive care unit (ICU), its utility in the context of asthma has not been definitively established. In this study, baseline data, albumin concentration, anion gap (AG) and 30-d mortality data were retrieved from the Medical Information Mart for Intensive Care IV database (MIMIC-IV) for patients with asthma in the intensive care unit. Receiver operating characteristic (ROC) curves were constructed to analyze the predictive ability of ACAG and AG. The risk of 30-day mortality among patients with ACAG and asthma was analyzed using a restricted cubic spline (RCS) plot. Decision curve analysis (DCA) was used to evaluate the clinical usefulness of ACAG as a prognostic factor for 30-day mortality. Subsequently, subgroup analysis was conducted to explore potential variations in the relationship between ACAG and 30-day mortality based on factors such as sex, age, whether the asthma was acute, and other co-morbidities. Our study reveals that ACAG is a significant independent predictor of 30-day mortality in asthmatic patients receiving intensive care. The area under the AUC curve for ACAG was found to be 0.703, which is higher than that of AG, indicating that ACAG has a better predictive ability for 30-day mortality in this population. Furthermore, higher levels of ACAG were found to be associated with increased risk of 30-day mortality in asthmatic patients. In addition, decision curve analysis (DCA) demonstrated that the net benefit of ACAG was greater than that of AG. These findings suggest that ACAG may be a valuable prognostic factor for predicting 30-day mortality in asthmatic patients in the ICU. Our study provides evidence that ACAG is associated with an increased risk of 30-d mortality and has better predictive value in patients with combined asthma who are admitted to the ICU than AG.

Deciphering the non-covalent interactions in the furan⋯hexane complex using rotational spectroscopy and theoretical analyses.

The rotational spectrum of a binary complex formed between furan and n-hexane was investigated using a chirped pulse Fourier transform microwave spectrometer in the range of 2-6 GHz. While furan has only one conformer, n-hexane exists in multiple conformations. The conformational landscape of the binary complex was systematically explored by using a semiempirical conformational search tool, namely CREST. The CREST conformational candidates were subjected to further geometry optimization and harmonic frequency calculations at the B3LYP-D3BJ/def2-TZVP level of theory, resulting in 34 minima within an energy window of 5 kJ mol-1. The three most stable furan⋯hexane minima all contain the most stable n-hexane conformer subunit and are separated by relatively low conformational conversion barriers. Additional calculations were carried out to support the conclusive identification of the global minimum structure responsible for the set of assigned rotational transitions. These include calculations at the B3LYP-D3BJ level with the aug-cc-pVTZ and 6-311++G(d,p) basis sets and the MP2/def2-TZVP level, as well as the single point energy calculations at the CCSD(T)-F12/cc-pVDZ level. Further non-covalent interaction and principal interacting orbital analyses show that the synergy of the πfuran → σ*hexane and σhexane → π*furan interactions plays an important role in stabilizing the observed furan-hexane conformer.

Metal Modulation: An Effortless Tactic for Refining Photoredox Catalysis in Living Cells.

The remarkable impact of photoredox catalytic chemistries has sparked a wave of innovation, opening doors to novel biotechnologies in the realm of catalytic antitumor therapy. Yet, the quest for novel photoredox catalysts (PCs) suitable for living systems, or the enhancement of catalytic efficacy in existing biocompatible PC systems, persists as a formidable challenge. Within this context, we introduce a readily applicable metal modulation strategy that significantly augments photoredox catalysis within living cells, exemplified by a set of metalloporphyrin complexes termed M-TCPPs (M = Zn, Mn, Ni, Co, Cu). Among these complexes, Zn-TCPP emerges as an exceptional catalyst, displaying remarkable photocatalytic activity in the oxidation of nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide phosphate (NADPH), and specific amino acids. Notably, comprehensive investigations reveal that Zn-TCPP's superior catalytic prowess primarily arises from the establishment of an efficient oxidative cycle for PC, in contrast to previously reported PCs engaged in reductive cycles. Moreover, theoretical calculations illuminate that amplified intersystem crossing rates and geometry alterations in Zn-TCPP contribute to its heightened photocatalytic performance. In vitro studies demonstrated that Zn-TCPP exhibits therapeutic potential and is found to be effective for photocatalytic antitumor therapy in both glioblastoma G98T cells and 3D multicellular spheroids. This study underscores the transformative role of "metal modulation" in advancing high-performance PCs for catalytic antitumor therapy, marking a significant stride toward the realization of this innovative therapeutic approach.

Wetting vs Droplet Aggregation: A Broadband Rotational Spectroscopic Study of 3-Methylcatechol⋠⋠⋠Water Clusters.

Two competing solvation pathways of 3-methylcatechol (MC), an atmospherically relevant aromatic molecule, with up to five water molecules were explored in detail by using a combination of broadband rotational spectroscopy and computational chemistry. Theoretically, two different pathways of solvation emerge: the commonly observed droplet pathway which involves preferential binding among the water molecules while the solute serves as an anchor point for the formation of a water cluster, and an unexpected wetting pathway which involves interactions between the water molecules and the aromatic face of MC, i.e., a wetting of the π-surface. Conclusive identification of the MC hydrate structures, and therefore the wetting pathway, was facilitated by rotational spectra of the parent MC hydrates and several H2 18 O and 13 C isotopologues which exhibit splittings associated with methyl internal rotation and/or water tunneling motions. Theoretical modelling and analyses offer insights into the tunneling and conversion barriers associated with the observed hydrate conformers and the nature of the non-covalent interactions involved in choosing the unusual wetting pathway.

Ultrathin Water Layer Conservation by "Nano-forest" in a Three-Dimensional Interface Regulates Energy Flow to Boost Solar Evaporation.

Solar-driven interfacial evaporation technology utilizes materials to form a thin layer on the water's surface, absorbs sunlight on this layer, completes the light-to-heat conversion, heats up the water, and vaporizes it. This greatly reduces energy loss to bulk water and greatly improves the evaporation rate for producing clean water. Additionally, three-dimensional (3D) evaporators are increasingly being applied in this field, and the cold surface generated by the rapid evaporation in the 3D evaporator can utilize environmental heat to achieve a net energy gain for the system. Both strategies improve the evaporation rate of the system, but 3D materials typically have high water contents and cannot avoid energy flow into non-evaporated water. To address this, we introduce the advantages of interfacial evaporation into 3D evaporation by constructing an evaporator with a highly conductive copper core skeleton and an outer layer of ultrathin water and by reasonably constructing interconnected evaporation frameworks. Investigating and optimizing the mutual influence of the ultrathin water layer on the framework, an evaporator with 40 pores per inch (ppi) can reach a maximum of 24.4 kg·m-2 h-1, indicating that 3D interfacial evaporators with ultrathin water layers concentrate energy flow to stimulate high evaporation rates. This strategy will promote the development of photothermal evaporation technology.

Rotational spectroscopy of hydrogen-bonded binary trifluoro-propanol conformers: conformational diversity, preference and abundances in a jet expansion.

The rich conformational landscape including the associated conformational conversion paths of the hydrogen-bonded binary 3,3,3-trifluoropropanol (TFP) aggregate was explored using chirped pulse Fourier transform microwave spectroscopy and computational chemistry. To appropriately identify the binary TFP conformers responsible for the five sets of candidate rotational transitions assigned, we established a set of important conformational assignment criteria. These include an extensive conformational search, good agreement between the experimental and theoretical rotational constants, relative magnitude of the three dipole moment components, and quartic centrifugal distortion constants, and observation and non-observation of the predicted conformers. Extensive conformational searches were carried out using CREST, a conformational search tool, producing hundreds of structural candidates. The CREST candidates were screened using a multitier approach and subsequently the low energy conformers (<25 kJ mol-1) were optimized at the B3LYP-D3BJ/def2-TZVP level, leading to 62 minima within an energy window of 10 kJ mol-1. Good agreement with the predicted spectroscopic properties mentioned above allowed us to clearly identify five binary TFP conformers as the molecular carriers. Particularly, a combined kinetic and thermodynamic model was developed, which provides a satisfactory explanation for the observation and non-observation of the low energy conformers predicted. The role of the intra- and intermolecular hydrogen bonding interactions in the stability ordering of the binary conformers is discussed.

Blending Low-Frequency Vibrations and Push-Pull Effects Affords Superior Photoacoustic Imaging Agents.

Photoacoustic imaging (PAI), a state-of-the-art noninvasive in vivo imaging technique, has been widely used in clinical disease diagnosis. However, the design of high-performance PAI agents with three key characteristics, i.e., near-infrared (NIR) absorption (λabs >800 nm), intense PA signals, and excellent photostability, remains a challenging goal. Herein, we present a facile but effective approach for engineering PAI agents by amplifying intramolecular low-frequency vibrations and enhancing the push-pull effect. As a demonstration of this blended approach, we constructed a PAI agent (BDP1-NEt2 ) based on the boron-dipyrromethene (BODIPY) scaffold. Compared with indocyanine green (ICG, an FDA-approved organic dye widely utilized in PAI studies; λabs =788 nm), BDP1-NEt2 exhibited a UV/Vis-NIR spectrum peaked at 825 nm, superior in vivo PA signal intensity and outstanding stability to offer improved tumor diagnostics. We believe this work provides a promising strategy to develop the next generation of PAI agents.

Infrared and vibrational circular dichroism spectra of methyl ß-D-glucopyranose in water: The application of the quantum cluster growth and clusters-in-a-liquid solvation models.

The infrared (IR) and vibrational circular dichroism (VCD) spectra of methyl ß-D-glucopyranose in water were measured. Both implicit and explicit solvation models were utilized to explain the observed spectra. The vast body of existing experimental and theoretical data suggested that about eight explicit water molecules are needed to account for the solvent effects, supported by the current Quantum Cluster Growth (QCG) analysis. Extensive manual and systematic conformational searches of the molecular target and its water clusters were carried out by using a recently developed conformational searching tool, conformer-rotamer ensemble sampling tool (CREST), and the microsolvation model in the associated QCG code. The Boltzmann averaged IR and VCD spectra of the methyl ß-D-glucopyranose-(water)n (n = 8) conformers in the PCM of water provide better agreement with the experimental ones than those with n = 0, 1, and 2. The explicit solvation with eight water molecules was shown to greatly modify the conformational preference of methyl ß-D-glucopyranose from its monomeric form. Further analyses show that the result is consistent with the existence of long-lived methyl ß-D-glucopyranose monohydrates with the additional explicit water effects being accounted for with the quantum mechanical treatment of the other seven close-by water molecules in the PCM of water.

Conformational Distributions of Phenyl ß-D-Glucopyranoside and Gastrodin in Solution by Vibrational Optical Activity and Theoretical Calculations.

The conformational landscapes of two highly flexible monosaccharide derivatives, namely phenyl ß-D-glucopyranoside (ph-ß-glu) and 4-(hydroxymethyl)phenyl ß-D-glucopyranoside, also commonly known as gastrodin, were explored using a combined experimental and theoretical approach. For the infrared, Raman, and the associated vibrational optical activity (VOA), i.e., vibrational circular dichroism and Raman optical activity, experiments of these two compounds in DMSO and in water were carried out. Extensive and systematic conformational searches were performed using a recently developed conformational searching tool called CREST (conformer-rotamer ensemble sampling tool) in the two solvents. Fourteen and twenty-four low-energy conformers were identified at the DFT level for ph-ß-glu and gastrodin, respectively. The spectral simulations of individual conformers were done at the B3LYP-D3BJ/def2-TZVPD level with the polarizable continuum model of the solvents. The VOA spectral features exhibit much higher specificity to conformational differences than their parent infrared and Raman. The excellent agreements achieved between the experimental and simulated VOA spectra allow for the extraction of experimental conformational distributions of these two carbohydrates in solution directly. The experimental percentage abundances based on the hydroxymethyl (at the pyranose ring) conformations G+, G-, and T for ph-ß-glu were obtained to be 15%, 75%, and 10% in DMSO and 53%, 40%, and 7% in water, respectively, in comparison to the previously reported gas phase values of 68%, 25%, and 7%, highlighting the important role of solvents in conformational preferences. The corresponding experimental distributions for gastrodin are 56%, 22%, and 22% in DMSO and 70%, 21%, and 9% in water.

Photon-Controlled Pyroptosis Activation (PhotoPyro): An Emerging Trigger for Antitumor Immune Response.

Pyroptosis refers to the process of gasdermin-mediated lytic programmed cell death (PCD) characterized by the release of pro-inflammatory cytokines. Our knowledge of pyroptosis has expanded beyond the cellular level and now includes extracellular responses. In recent years, pyroptosis has attracted considerable attention due to its potential to induce host immunity. For instance, at the 2022 International Medicinal Chemistry of Natural Active Ligand Metal-Based Drugs (MCNALMD) conference, numerous researchers demonstrated an interest in photon-controlled pyroptosis activation ("PhotoPyro"), an emerging pyroptosis-engineered approach for activating systemic immunity via photoirradiation. Given this enthusiasm, we share in this Perspective our views on this emerging area and expound on how and why "PhotoPyro" could trigger antitumor immunity (i.e., turning so-called "cold" tumors "hot"). In doing so, we have tried to highlight cutting-edge breakthroughs in PhotoPyro while suggesting areas for future contributions. By providing insights into the current state of the art and serving as a resource for individuals interested in working in this area, it is hoped that this Perspective will set the stage for PhotoPyro to evolve into a broadly applicable cancer treatment strategy.

Stereochemical Properties of Two Schiff-Base Transition Metal Complexes and Their Ligand by Using Multiple Chiroptical Spectroscopic Tools and DFT Calculations.

Two transition metal complexes were synthesized with Ni(II) and Cu(II) using a tetradentate Schiff-base ligand, (R,R) and (S,S)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine. The stereochemical properties of the ligand and the metal complexes were investigated using a combined experimental and theoretical approach. Multiple spectroscopic techniques, which include IR, vibrational circular dichroism (VCD), UV-Vis and electronic circular dichroism (ECD), as well as Raman and the newly discovered ECD-circularly polarized Raman (i.e., eCP-Raman) spectroscopies were utilized. The good agreement achieved between the experimental and simulated IR, VCD, UV-Vis and ECD spectra of the ligand allowed one to identify the presence of three main ligand conformers in solution, thanks, especially to the high VCD sensitivity to the conformations associated with the tertbutyl groups. The helicity of the metal complexes was identified to be M and P for those with the (R,R) and (S,S) ligands, respectively. Furthermore, eCP-Raman measurements were carried out for the two metal complexes under (near) resonance. Their induced solvent chiral Raman features were explained, and the potential application of eCP-Raman was discussed.

Cutting Off H+ Leaks on the Inner Mitochondrial Membrane: A Proton Modulation Approach to Selectively Eradicate Cancer Stem Cells.

Cancer stem cells (CSCs) are associated with the invasion and metastatic relapse of various cancers. However, current cancer therapies are limited to targeting the bulk of primary tumor cells while remaining the CSCs untouched. Here, we report a new proton (H+) modulation approach to selectively eradicate CSCs via cutting off the H+ leaks on the inner mitochondrial membrane (IMM). Based on the fruit extract of Gardenia jasminoides, a multimodal molecule channel blocker with high biosafety, namely, Bo-Mt-Ge, is developed. Importantly, in this study, we successfully identify that mitochondrial uncoupling protein UCP2 is closely correlated with the stemness of CSCs, which may offer a new perspective for selective CSC drug discovery. Mechanistic studies show that Bo-Mt-Ge can specifically inhibit the UCP2 activities, decrease the H+ influx in the matrix, regulate the electrochemical gradient, and deplete the endogenous GSH, which synergistically constitute a unique MoA to active apoptotic CSC death. Intriguingly, Bo-Mt-Ge also counteracts the therapeutic resistance via a two-pronged tactic: drug efflux pump P-glycoprotein downregulation and antiapoptotic factor (e.g., Bcl-2) inhibition. With these merits, Bo-Mt-Ge proved to be one of the safest and most efficacious anti-CSC agents, with ca. 100-fold more potent than genipin alone in vitro and in vivo. This study offers new insights and promising solutions for future CSC therapies in the clinic.

Conformations of Steroid Hormones: Infrared and Vibrational Circular Dichroism Spectroscopy.

Steroid hormone molecules may exhibit very different functionalities based on the associated functional groups and their 3D arrangements in space, i.e., absolute configurations and conformations. Infrared (IR) and vibrational circular dichroism (VCD) spectra of four different steroid hormones, namely dehydroepiandrosterone (DHEA), 17α-methyltestosterone (MTTT), (16α,17)-epoxyprogesterone (Epoxy-P4), and dehydroepiandrosterone acetate (AcO-DHEA), were measured in deuterated dimethyl sulfoxide and some also in carbon tetrachloride. Extensive conformational searches were carried out using the recent developed conformer-rotamer ensemble sampling tool (CREST) which also accounts for solvent effects using an implicit solvation model. All the CREST conformational candidates were then reoptimized at the B3LYP-D3BJ/def2-TZVPD with the PCM of solvent. The good agreements between the experimental IR and VCD spectra and the theoretical simulations provide a conclusive information about their conformational distribution and absolute configurations. The experimental and theoretical IR and VCD spectra of AcO-DHEA in the carbonyl and alkene stretching region showed some discrepancies, and the possible causes related to solvent effects, large amplitude motions and levels of theory used in the modelling were explored in detail. As part of the investigation, additional calculations at the B3LYP-D3BJ/6-31++G (2d,p) and B3LYP-D3BJ/cc-pVTZ levels, as well as some 'mixed' calculations with the double-hybrid functional B2PLYP-D3 were also carried out. The results indicate that the double-hybrid functional is important for predicting the correct IR band pattern in the carbonyl and alkene stretching region.