Clinical research progress of novel antituberculosis drugs on multidrug-resistant tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) has become a critical challenge to public health, and the prevention and treatment of MDR-TB are of great significance in reducing the global burden of tuberculosis. How to improve the effectiveness and safety of chemotherapy for MDR-TB is a pressing issue that needs to be addressed in tuberculosis control efforts. This article provides a comprehensive review of the clinical application of new antituberculosis drugs in MDR-TB, aiming to provide a scientific basis for the prevention and treatment strategy of MDR-TB.

Full-length transcriptome profiling of Acanthopanax gracilistylus provides new insight into the kaurenoic acid biosynthesis pathway.

Acanthopanax gracilistylus is a deciduous plant in the family Araliaceae, which is commonly used in Chinese herbal medicine, as the root bark has functions of nourishing the liver and kidneys, removing dampness and expelling wind, and strengthening the bones and tendons. Kaurenoic acid (KA) is the main effective substance in the root bark of A. gracilistylus with strong anti-inflammatory effects. To elucidate the KA biosynthesis pathway, second-generation (DNA nanoball) and third-generation (Pacific Biosciences) sequencing were performed to analyze the transcriptomes of the A. gracilistylus leaves, roots, and stems. Among the total 505,880 isoforms, 408,954 were annotated by seven major databases. Sixty isoforms with complete open reading frames encoding 11 key enzymes involved in the KA biosynthesis pathway were identified. Correlation analysis between isoform expression and KA content identified a total of eight key genes. Six key enzyme genes involved in KA biosynthesis were validated by real-time quantitative polymerase chain reaction. Based on the sequence analysis, the spatial structure of ent-kaurene oxidase was modeled, which plays roles in the three continuous oxidations steps of KA biosynthesis. This study greatly enriches the transcriptome data of A. gracilistylus and facilitates further analysis of the function and regulation mechanism of key enzymes in the KA biosynthesis pathway. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01436-7.

Full-length transcriptome analysis provides insights into flavonoid biosynthesis in Ranunculus japonicus.

Ranunculus japonicus Thunb. is a traditional Chinese herb. Plants in the genus Ranunculus are generally rich in flavonoids, which have antibacterial, anti-infective, and other pharmacological effects. However, owing to the lack of reference genomes, little is known about the flavonoid biosynthetic pathway in R. japonicus. In this study, PacBio isoform sequencing (PacBio iso-seq) and DNA nanoball sequencing (DNB-seq) were combined to build a full-length transcriptome database for three different tissues of R. japonicus. A total of 395,402 full-length transcripts were obtained, of which 308,474 were successfully annotated. A Kyoto Encyclopedia of Genes and Genomes analysis identified 29 differentially expressed genes encoding nine key enzymes for flavonoid biosynthesis. Correlation analysis indicated that flavanone 3-hydroxylase and flavonol synthase genes might have key roles in the accumulation of flavonoid substances in the different tissues of R. japonicus. The structures of chalcone synthase and chalcone isomerase enzymes were spatially modeled. Reverse-transcription quantitative PCR was used to verify gene expression levels of key enzymes associated with flavonoid biosynthesis. In addition, 22 MYB transcription factors involved in flavonoid biosynthesis and phenylpropanoid biosynthesis were discovered. The reliable transcriptomic data from this study provide genetic information about R. japonicus as well as insights into the molecular mechanism of flavonoid biosynthesis. The results also provide a basis for developing the medicinal value R. japonicus.

Full-length transcriptome sequencing provides new insights into the complexity of flavonoid biosynthesis in Glechoma longituba.

Glechoma longituba has been frequently used in treating urolithiasis and cholelithiasis due to the presence of flavonoids, which are its major bioactive constituents. However, research on the molecular background of flavonoid biosynthesis in G. longituba is limited. In this study, we used single-molecule real-time combined with next-generation sequencing technologies to construct the complete transcriptome of G. longituba. We identified 404,648 non-redundant transcripts, including 249,697 coding sequences, 197,811 simple sequence repeats, 174,846 long noncoding RNA, and 176,554 coding RNA. Moreover, we functionally annotated 346,218 isoforms (85.56%) and identified 86,528 differentially expressed genes. We also identified 55 non-redundant full-length isoforms related to the flavonoid biosynthetic pathway. Pearson correlation analysis revealed that the expression levels of some key genes of the flavonoid biosynthesis pathway were significantly positively correlated with the flavonoid metabolites. Furthermore, we performed bioinformatics analysis (sequence and structural) of isoform_47029 (encoding flavanone 3-hydroxylase) and isoform_53692 (encoding flavonol synthase) to evaluate their potential biological functions. Finally, we validated gene expression levels of 12 flavonoid-related key enzyme genes using quantitative real-time PCR. Overall, this study provides full-length transcriptome information on G. longituba for the first time and valuable molecular resources for further research on the medicinal properties of this plant.

Largely Color-Tuning Prompt and Delayed Fluorescence: Dinuclear Cu(I) Halide Complexes with tert-Amines and Phosphines.

Luminescent copper(I) halide complexes with bi- and tridentate rigid ligands have gained wide research interests. In this paper, six tetracoordinate dinuclear copper(I) halide complexes, Cu2X2(ppda)2 [ppda = 2-[2-(dimethylamino)phenyl(phenyl)phosphino]-N,N-dimethylaniline, X = I (1), Br (2), Cl (3)] and Cu2X2(pfda)2 [pfda = 2-[2-(dimethylamino)-4-(trifluoromethyl)phenyl(phenyl)phosphino]-N,N-dimethyl-5-trifluoromethylaniline, X = I (4), Br (5), Cl (6)], were successfully prepared and systematically characterized on their structures and photophysical properties. Complexes 1-5 have a centrosymmetric form with a planar Cu2X2 unit, and complex 6 has a mirror symmetry form with a butterfly-shaped Cu2X2. Solid complexes 1, 4, and 5 emit delayed fluorescence at room temperature, intense blue to greenish yellow (λmax = 443-570 nm) light, and their peak wavelengths are located at 443-570 nm with microsecond lifetimes (τ = 0.4-19.2 µs, ΦPL = 0.05-0.48). Complexes 2, 3, and 6 show prompt fluorescence, very weak yellowish green to yellow (λmax = 534-595 nm) emission with peak wavelengths at 534-595 nm, and lifetimes in nanoseconds (τ = 4.4-9.3 ns, ΦPL < 0.0001). (Metal + halide) to ligand and intraligand charge transitions are the main origin of the emission of the complexes. Solution-processed, complex-4-based nondoped and doped devices emit yellow green light with CIE coordinated at (0.41, 0.51), a maximum EQE up to 0.17%, and luminance reaching 75.52 cd/m2.

Stereoselective synthesis of N-ethyl-2-arylvinyl-5-methyl fulleropyrrolidines: reaction of [60]fullerene with aromatic aldehydes and triethylamine/diethylamine in the absence or presence of manganese(iii) acetate.

The reaction of [60]fullerene with aromatic aldehydes and triethylamine/diethylamine in the absence or presence of manganese(iii) acetate under air conditions afforded a series of N-ethyl-2-arylvinyl-5-methyl fulleropyrrolidines in moderate to good yields, which would be difficult to synthesize by reported protocols. The in situ generation of arylvinyl aldehydes by the aldol reaction of aromatic aldehydes with acetaldehyde from an unusual C-N bond cleavage of triethylamine/diethylamine played a crucial role in the successful preparation of the corresponding fulleropyrrolidines. Depending on the reaction conditions, both cis and trans isomers of fulleropyrrolidines could be selectively synthesized. Cis isomers as major products could be obtained by reacting with triethylamine at 160 °C without the addition of manganese(iii) acetate, while trans isomers as major products, with rare exceptions, could be observed via the reaction with diethylamine at 120 °C under the assistance of manganese(iii) acetate. Moreover, the in situ generated arylvinyl aldehydes displayed higher reactivity towards diethylamine as compared with aryl aldehydes, leading to the formation of arylvinyl-substituted fulleropyrrolidines. A plausible formation mechanism for fulleropyrrolidines was provided based on the experimental observations.

Synthesis of 2-Aryl-5-alkyl-fulleropyrrolidines: Metal-Free-Mediated Reaction of [60]Fullerene with Aromatic Aldehydes and Inactive Primary Amines.

The metal-free-mediated thermal reaction of [60]fullerene with aromatic aldehydes and inactive primary amines bearing electron-donating groups at the α-position afforded a series of 2-aryl-5-alkyl-fulleropyrrolidines, including the scarce 2-aryl-5-benzyl-fulleropyrrolidines as a mixture of cis and trans isomers. With rare exceptions, the mixture of cis and trans isomers could be easily isolated by column chromatography, with a preference of cis isomers as major products. A plausible mechanism for the formation of fulleropyrrolidines is also proposed.

A Protocol for the Preparation of 2,5-Diaryl Fulleropyrrolidines: Thermal Reaction of [60]Fullerene with Aromatic Aldehydes and Arylmethanamines.

Thermal reaction of [60]fullerene with various arylmethanamines in the presence of aromatic aldehydes under air conditions afforded a series of rare 2,5-diaryl fulleropyrrolidines. Intriguingly, the obtained fulleropyrrolidines exhibited different stereoselectivity. N-unsubstituted arylmethanamines exclusively produced 2,5-diaryl fulleropyrrolidines as cis isomers, while N-substituted arylmethanamines with rare exceptions always gave 2,5-diaryl fulleropyrrolidines as trans isomers. Theoretical calculations at the level of B3LYP/6-31G (d,p) were employed to elucidate the stereoselectivity of N-substituted 2,5-diaryl fulleropyrrolidines as trans isomers by investigating the transition-state structures of different cycloaddition pathways.

Energy relaxation and separation of a hot electron-hole pair in organic aggregates from a time-dependent wavepacket diffusion method.

The time-dependent wavepacket diffusive method [X. Zhong and Y. Zhao, J. Chem. Phys. 138, 014111 (2013)] is extended to investigate the energy relaxation and separation of a hot electron-hole pair in organic aggregates with incorporation of Coulomb interaction and electron-phonon coupling. The pair initial condition generated by laser pulse is represented by a Gaussian wavepacket with a central momentum. The results reveal that the hot electron energy relaxation is very well described by two rate processes with the fast rate much larger than the slow one, consistent with experimental observations, and an efficient electron-hole separation is accomplished accompanying the fast energy relaxation. Furthermore, although the extra energy indeed helps the separation by overcoming the Coulomb interaction, the width of initial wavepacket is much sensitive to the separation efficiency and the narrower wavepacket generates the more separated charges. This behavior may be useful to understand the experimental controversy of the hot carrier effect on charge separation.

Mo-doping and construction of the heterostructure between NiFe LDH and NiSx co-trigger the activity enhancement for overall water splitting.

To reduce the preparation cost of high-purity hydrogen, it is necessary to search suitable non-precious metal catalysts with high activity and robust stability. Herein, two means (heteroatom-doping and the heterostructure construction) were adopted together to improve the dual-function activity of NiFe LDH which was widely used in water electrolysis. Mo doped NiFe LDH nanoflowers were firstly generated by hydrothermal reaction, and then NiSx was modified on the petals via electrodeposition. Finally, the obtained NF/Mo-NiFe LDH/NiSx with large electrochemical active area exhibits the expected electrochemical performance with the overpotential at 100 mA cm-2 of 169 and 249 mV for hydrogen evolution (HER) and oxygen evolution reaction (OER) respectively. Assembling NF/Mo-NiFe LDH/NiSx into a two-electrode device for the integral water electrolysis, it just requires a cell voltage of 1.69 V to drive a current density of 100 mA cm-2, and keeps stable after 50-hour continuous operation in 1.0 M KOH. Mo-doping not only regulates the electronic structure of the transition metals and reduces the energy barrier of HER intermediates, but also facilitates the generation of reactive sites for OER. Meanwhile, the construction of heterointerface ensures the synergism between NiSx and Mo-NiFe LDH and accelerates the electron transfer across interfaces, thus enhancing the bifunctional performance.

Non-Markovian stochastic Schrödinger equation at finite temperatures for charge carrier dynamics in organic crystals.

A new non-Markovian stochastic Schrödinger equation at finite temperatures is presented to correctly describe charge carrier dynamics in organic molecular crystals. The electron-phonon interactions in both site energies and electronic couplings are incorporated by the time-dependent complex-valued random fluctuations which are generated from corresponding spectral density functions. The approach is thus easily extended to investigate coherent-to-hopping charge transfer in systems with thousands of molecular sites. The capability of present approach is demonstrated by numerical simulations of carrier dynamics in the spin-boson model and a realistic Fenna-Matthews-Olson complex. The results manifest that the non-Markovian effect and complex-valued random forces are essential to guarantee the detailed balance. In an application to a long-chain donor-acceptor system, it is also interesting to find a property of coherent-to-hopping charge transfer from temperature dependence of diffusion coefficients.

Ameliorative Effects of Lactobacillus paracasei L14 on Oxidative Stress and Gut Microbiota in Type 2 Diabetes Mellitus Rats.

Bioprospecting of more novel probiotic strains has attained continuous interest. This study aimed to investigate the beneficial effects of Lactobacillus paracasei strain L14, an isolate from a traditional Chinese dairy product, on type 2 diabetes mellitus (T2DM) rats. Preventive supplementation of strain L14 showed excellent anti-diabetic effects on high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM rats. It significantly reduced hyperglycemia, protected pancreatic ß-cell and liver function, and ameliorated oxidative stress while considerably improving dyslipidemia and inflammation. Furthermore, the strain modulated the gut microbiota to alleviate gut dysbiosis. Interestingly, most of these biochemical parameters could even restore to normal levels by the intervention of strain L14. The whole-genome sequencing of L14 was performed to provide a critical molecular basis for its probiotic activities. Genes related to antioxidant systems and other beneficial microbial metabolites like exopolysaccharides (EPS) biosynthesis were found. This study demonstrates that probiotic L. paracasei L14 has good potential for applications in functional food and pharmaceutical industries.

Electron mobilities of n-type organic semiconductors from time-dependent wavepacket diffusion method: pentacenequinone derivatives.

The electron mobilities of two n-type pentacenequinone derivative organic semiconductors, 5,7,12,14-tetraaza-6,13-pentacenequinone (TAPQ5) and 1,4,8,11-tetraaza-6,13-pentacenequinone (TAPQ7), are investigated with use of the methods of electronic structure and quantum dynamics. The electronic structure calculations reveal that the two key parameters for the control of electron transfer, reorganization energy and electronic coupling, are similar for these two isomerization systems, and the charge carriers essentially display one-dimensional transport properties. The mobilities are then calculated by using the time-dependent wavepacket diffusion approach in which the dynamic fluctuations of the electronic couplings are incorporated via their correlation functions obtained from molecular dynamics simulations. The predicted mobility of TAPQ7 crystal is about six times larger than that of TAPQ5 crystal. Most interestingly, Fermi's golden rule predicts the mobilities very close to those from the time-dependent wavepacket diffusion method, even though the electronic couplings are explicitly large enough to make the perturbation theory invalid. The possible reason is analyzed from the dynamic fluctuations.

The Aptamer Ob2, a novel AChE inhibitor, restores cognitive deficits and alleviates amyloidogenesis in 5×FAD transgenic mice.

Loss of cerebral cholinergic neurons and decreased levels of acetylcholine (ACh) are considered to be major factors causing cognitive dysfunction in Alzheimer's disease (AD). Abnormally elevated levels of acetylcholinesterase (AChE) resulting in decreased levels of ACh are common in AD patients; thus, AChE inhibitors (AChEIs) are widely used for the treatment of AD. In our previous work, we acquired DNA aptamers Ob1, Ob2, and Ob3 against human brain AChE from systematic evolution of ligands by exponential enrichment (SELEX). In this study, we investigated the effect of these aptamers on learning and memory abilities, as well as the underlying mechanism in a 5×FAD transgenic AD mouse model. Here, we showed that only aptamer Ob2 exhibits a good inhibitory effect on both mouse and human AChE activity. In addition, chronic treatment with aptamer Ob2 significantly improved cognitive ability of 5×FAD mice in the Morris water maze. Moreover, the mechanism of aptamer Ob2 in 5×FAD mice may be associated with its inhibition of AChE activity, alleviation of the levels of Aß by lowering the expression of ß-secretase (BACE1), and activation of astrocytes in the brains of 5×FAD mice. These results indicate that aptamer Ob2 exhibits potential as an effective AChEI for the treatment of AD.

Discovery of 2-Methyl-2-(4-(2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-6-yl)-1H-naphtho[1,2-d]imidazol-1-yl)phenyl)propanenitrile as a Novel PI3K/mTOR Inhibitor with Enhanced Antitumor Efficacy In Vitro and In Vivo.

PI3K/Akt/mTOR signaling pathway is a validated drug target for cancer treatment that plays a critical role in controlling tumor growth, proliferation, and apoptosis. However, no FDA-approved PI3K/mTOR dual inhibitor exists. Thus, a candidate with a better curative effect and lower toxicity is still urgently needed. Herein, we design, synthesize, and evaluate compounds belonging to a novel series of 2-methyl-1H-imidazo[4,5-c]quinoline scaffold derivatives as PI3K/mTOR dual inhibitors. Among them, compound 8o was identified as a novel candidate with excellent kinase selectivity. It manifested remarkable antiproliferative activities against SW620 and HeLa cells. Western blot and immunohistochemical analysis results proved that 8o could regulate the PI3K/AKT/mTOR signaling pathway by inhibiting the phosphorylation of AKT and S6 proteins. Additionally, 8o presented a favorable pharmacokinetic property (oral bioavailability of 76.8%) and significant antitumor efficacy in vivo without obvious toxicity. Collectively, these results indicated that 8o is a promising agent for cancer treatment and merits further development.

Effect of group electronegativity on electron transfer in bis(hydrazine) radical cations.

The radical cation of 4,10-ditert-butyl-5,9-diisopropyl-4,5,9,10-tetraazatetracyclo[6.2.2.2]-tetradecane (sBI4T(+)), as well as its substituted bis(hydrazine) radical cations, is chosen for the investigation of the electronegativity dependence of its intramolecular electron transfer. To do so, two parameters, reorganization energy and electronic coupling, are calculated with several ab initio approaches. It is found that the electronic couplings decrease with the increase of the group electronegativity while the reorganization energies do not show an explicit dependency. Furthermore, Marcus formula is employed to reveal those effect on the electron transfer rates. The predicted rates of electron transfer generally decrease with increasing group electronegativity, although not monotonically.

Charge carrier dynamics in phonon-induced fluctuation systems from time-dependent wavepacket diffusion approach.

A time-dependent wavepacket diffusion method is proposed to deal with charge transport in organic crystals. The electron-phonon interactions in both site energies and electronic couplings are incorporated by the time-dependent fluctuations which are generated from the corresponding spectral density functions. The numerical demonstrations reveal that the present approach predicts the consistent charge carrier dynamics with the rigorous quantum approaches. In addition, the diffusion coefficients obtained from the Marcus formula are well reproduced at the weak electronic coupling and high temperature limits. It is also found that the charge mobility feature of the crossover from the band-like to the hopping-type cannot be predicted from the fluctuations induced by the linear electron-phonon interactions with an Ohmic spectral density; however, it indeed appears as the electronic coupling fluctuation exponentially depends on the nuclear coordinates. Finally, it should be noted that although the present approach neglects the imaginary fluctuation, it essentially incorporates the coherent motion of the charge carrier and quantum effect of the phonon motion with a broad regime of the fluctuations for symmetric systems. Besides, the approach can easily be applied to systems having thousands of sites, which allows one to investigate charge transport in nanoscale organic crystals.

Luminescence Change from Orange to Blue for Zero-Dimensional Cs2 InCl5 (H2 O) Metal Halides in Water and a New Post-doping Method.

Zero-dimensional metal halides have attracted much attention due to their attractive photoelectric properties. Here, we propose a new strategy of synthesizing metal halides crystals by recrystallization in water. The as-synthesized Cs2 InCl5 (H2 O)-orange crystals are dissolved and recrystallized in water (Cs2 InCl5 (H2 O)-blue), with its photoluminescence (PL) changing from orange to blue, both of which are derived from self-trapping excitons (STEs). The time-resolved photoluminescence (TRPL) spectrum of Cs2 InCl5 (H2 O)-blue shows that it has an ultralong lifetime up to milliseconds (τ=52.98 ms), which is expected to be applied in biological sensors. The photoluminescence quantum yield (PLQY) increases from 2.25% to 11.61% in the self-assembly process. By using a post-doping method, the PL of crystals turns into red when we introduce Mn2+ as dopant while there is no obvious change upon using a traditional solvent-thermal method. Recrystallization in water and post-doping provide a new perspective for the synthesis and doping of metal halides.

Discovery of a PROTAC targeting ALK with in vivo activity.

Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. To overcome the drug resistance, proteolysis targeting chimeras (PROTACs) could be an alternative strategy. In this study, a series of ALK degraders were designed and synthesized. The degraders were developed through the conjugation of LDK378 and CRBN E3 ubiquitin ligase ligands. Among all the molecules, compound B3 showed potent selective inhibitory activity to ALK and can decrease the cellular levels of ALK fusion proteins in a concentration- and time-dependent manner in H3122 cell line. Meanwhile, B3 showed improved anticancer activity in vitro comparing with LDK378 and the antiproliferative activity to xenograft tumor model was acceptable. All the results demonstrated that ALK degrader B3 with in vitro and in vivo anti-cancer activities was valuable for further investigation.

Discovery of a novel covalent CDK4/6 inhibitor based on palbociclib scaffold.

Cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved in dynamic regulation of cell cycle, play an indispensable role in controlling the tumor growth. Here, based on the scaffold of palbociclib, we designed and synthesized a series of covalent CDK4/6 inhibitors that targeted amino acid Thr107. The optimized compound C-13 exhibited potent in vitro anticancer activity against CDK4/6 with high selectivity over CDK4/6. Moreover, C-13 showed significant tumor growth inhibition in MDA-MB-231 tumor xenograft model (TGI of 93.49% at dose of 40 mg/kg) without causing significant weight loss and toxicity during the treatment period.