Dual Activity Research Articles

Degradation of Prazosin by using Newer Dual Activity Hydrodynamic Cavitation Reactors

Degradation of Prazosin by using Newer Dual Activity Hydrodynamic Cavitation Reactors

Rational Design and Optimization of the Band Gap and p-Type Doping in High-Efficiency CdTe Solar Cells through CuSeCN Treatment.

Broadening the alloyed CdSexTe1-x region in the absorber layer is the key to preparing highly efficient CdTe-based solar cells (SCs). With CdSe prejunction doping, the diffusion distance via the non-in situ Se doping method is restricted, and the doping ions are difficult to completely diffuse through the whole absorber layer. Moreover, the commonly used p-type back contact material CuSCN shows efficient copper doping characteristics, but the S element is not an ideal doping source for the CdTe absorber. Thus, it is demanding to develop new materials with dual activation of copper and Se. In this paper, on the one hand, CuSeCN was used as a Se doping source on the back surface of the absorber to successfully form p-CdSeTe with a band gap of 1.438 eV. On the other hand, as an emerging copper-treated material, CuSeCN is able to enhance the carrier extraction rate and lower the Schottky barrier of the device, which exhibits similar hole activation performance to CuSCN. In addition, CdTe thin-film devices treated with CuSeCN exhibit higher PCEs than those of devices treated with a CuSCN/CdSe double layer. After optimizing the experimental conditions, the short current density of CuSeCN-doped CdTe thin-film solar cells increased from 28.03 to 30.02 mA/cm2, the FF increased from 58.11 to 70.06%, and the power conversion efficiency was 17.48%. These results confirmed that CuSeCN is a promising candidate for both efficient carrier doping and lowering the band gaps of CdTe-based SCs.

Perturbation of Pseudomonas aeruginosa peptidoglycan recycling by anti-folates and design of a dual-action inhibitor.

To combat the alarming global increase in superbugs amid the simultaneous scarcity of new drugs, we can create synergistic combinations of currently available antibiotics or chimeric molecules with dual activities, to minimize resistance. Here we show that older anti-folate drugs synergize with specific cell wall biosynthesis inhibitors to kill the priority pathogen, Pseudomonas aeruginosa. Anti-folate drugs caused a dose-dependent loss of rod cell shape followed by explosive lysis, and synergized with β-lactams that target D,D-carboxypeptidases required to tailor the cell wall. Anti-folates impaired cell wall recycling and subsequent downstream expression of the chromosomally encoded β-lactamase, AmpC, which normally destroys β-lactam antibiotics. Building on the anti-folate-like scaffold of a metallo-β-lactamase inhibitor, we created a new molecule, MLLB-2201, that potentiates β-lactams and anti-folates and restores meropenem activity against metallo-β-lactamase-expressing Escherichia coli. These strategies are useful ways to tackle the ongoing rise in dangerous bacterial pathogens.

Bivalent OX40 Aptamer and CpG as Dual Agonists for Cancer Immunotherapy.

Cancer immunotherapy has revolutionized cancer treatment by harnessing the body's immune system to recognize and attack tumors. Over the past 25 years, the use of blocking antibodies has fundamentally transformed the landscape of cancer therapy. However, despite extensive research, agonist antibodies targeting costimulatory receptors such as ICOS, GITR, OX40, CD27, and 4-1BB have consistently underperformed in clinical trials over the past 15 years, failing to meet the anticipated success. One reason the agonist antibodies failed is that researchers escalated the dose to the highest tolerable level, which can lead to cell exhaustion, especially when used as a single agent. In this study, we introduced novel in situ therapeutic agents by combining a bivalent RNA aptamer of OX40, biROX40, which binds to two copies of the OX40 receptor as an agonist, with CpG, a toll-like receptor 9 (TLR9) immune stimulator. These agents were specifically designed for lymphoma treatment, with the dose reduced to the lowest bioactive amount to maximize efficacy while minimizing potential side effects. BiROX40 and CpG exhibited a dual immune activation effect and demonstrated a synergistic response even at extremely low dose of 0.32 mg/kg (5.75 μg per mouse) for biROX40 and moderate dose of 1.39 mg/kg (25 μg per mouse) for CpG, resulting in remarkable antitumor efficacy. This effect was achieved through the promotion of intratumoral CD8+ T cell proliferation and cytokine secretion, inhibition of regulatory T cell (Treg) proliferation, and enhanced generation and proliferation of memory T cells in immune organs. The agonistic effects of these reagents led to tumor regression not only at the treated sites but also at distant, nontreated locations in the animal models. This outcome highlighted the induction of a robust systemic antitumor immune response, which effectively suppressed tumor recurrence. This in situ combination therapy, utilizing low-dose biROX40 alongside CpG, offers a straightforward and widely applicable strategy to enhance immune responses in cancer immunotherapy. This approach overcomes the limitations of high-dose single-agent anti-OX40 therapies (whether antibodies or aptamers), including immune cell exhaustion and diminished efficacy.

Synthesis, Structural Modification, and Antismall Cell Lung Cancer Activity of 3-Arylisoquinolines with Dual Inhibitory Activity on Topoisomerase I and II.

To overcome the compensatory effect between Topo I and II, one of the reasons accounting for the resistance of SCLC patients, we are pioneering the use of 3-arylisoquinolines to develop dual inhibitors of Topo I/II for the management of SCLC. A total of 46 new compounds were synthesized. Compounds 3g (IC50 = 1.30 μM for NCI-H446 cells and 1.42 μM for NCI-H1048 cells) and 3x (IC50 = 1.32 μM for NCI-H446 cells and 2.45 μM for NCI-H1048 cells) were selected for detailed pharmacological investigation, due to their outstanding cytotoxicity and dual Topo I and II inhibitory activity. 3g and 3x effectively prevent SCLC cell proliferation, invasion, and migration in vitro, byinducing mitochondrial apoptosis and inhibiting the PI3K/Akt/mTOR pathway. Their in vivo tumor inhibition rate is comparable to etoposide with lower toxicity. These results indicated their potential therapeutic values as dual Topo I and II inhibitors for treating SCLC.

Dual enzymatic activities of potato patatin: esterase and lipase characterization

Dual enzymatic activities of potato patatin: esterase and lipase characterization

Metabolites, Biotransformation, and Plant-Growth Dual Regulatory Activity from Aspergillus nishimurae Uncovered by the Fermentation Interaction with a Host.

One new azaphilone derivative (1) from Aspergillus nishimurae in ordinary medium, one new phthalide derivative (8), a microbial transformation product of Angelica sinensis ingredients by A. nishimurae, a pair of new austdiol enantiomers (+)-9 and (-)-9, one new epsilon-caprolactone derivative (10), and one new ophiobolin-type sesterterpenoid (13) from the A. nishimurae in host medium were reported. The structures were determined by spectroscopic analysis and single-crystal X-ray diffraction. Compounds 1-3 could completely inhibit the germination of rice seeds at 50 μg/mL, which is higher than that of the positive control. The mixture of compounds 8+2 represented an approximately 84% increase in root length at 20 μg/mL compared with that of phytotoxic compound 2. Compounds 8 and 16 led to approximately 39 and 7% increases in root length at 5 μg/mL compared with those of untreated rice seeds. Fermentation interactions between endophytes and host constituents induced cryptic metabolite, plant growth inhibiting, and plant growth promoting activities.

Dual Activation Modes Enable Bifunctional Catalysis of Aldol Reactions by Flexible Dihydrazides.

Hydrazides are known to catalyze reactions of α,β-unsaturated aldehydes via transient iminium formation. The iminium intermediate displays enhanced electrophilicity, which facilitates conjugate additions and cycloadditions. We observed that a hydrazide embedded in a seven-membered ring catalyzes homoaldol condensation of a simple aldehyde in a process that displays an approximate second-order dependence on the hydrazide. This finding suggests a dual activation mechanism involving both iminium and enamine intermediates. The unexpected nucleophilic activation mode led us to examine a series of simple dihydrazides for bifunctional catalysis of the aldol condensation. The two cyclic hydrazide units were connected via linear polymethylene linkers, which are inherently flexible. Substantial increases in initial reaction rate, relative to a monohydrazide, were observed for polymethylene linkers of sufficient length, with a maximum at 10 methylenes. Reactions promoted by this dihydrazide displayed an approximate first-order dependence on catalyst concentration, which suggested a bifunctional catalytic mechanism. Even for a dihydrazide with an 18-methylene linker, a substantial increase in relative initial rate was observed. These observations show that significant coordination can be achieved between two catalytically active moieties even when these moieties are connected via many flexible bonds.

Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach.

Dual activation of the TLR7 and TLR8 pathways leads to the production of type I interferon and proinflammatory cytokines, resulting in efficient antigen presentation by dendritic cells to promote T-cell priming and antitumor immunity. We developed a novel series of TLR7/8 dual agonists with varying ratios of TLR7 and TLR8 activity for use as payloads for an antibody-drug conjugate approach. The agonist-induced production of several cytokines in human whole blood confirmed their functional activity. Structure-activity relationship studies guided by structure-based drug design are described.

Molecular and structural basis of a subfamily of PrfH rescuing both the damaged and intact ribosomes stalled in translation.

In bacteria, spontaneous mRNAs degradation and ribotoxin-induced RNA damage are two main biological events that lead to the stall of protein translation. The ubiquitous trans-translation system as well as several alternative rescue factors (Arfs) are responsible for rescuing the stalled ribosomes caused by truncated mRNAs that lack the stop codons. To date, protein release factor homolog (PrfH) is the only factor known to rescue the stalled ribosome damaged by ribotoxins. Here we show that a subfamily of PrfH, exemplified by PrfH from Capnocytophaga gingivalis ( Cg PrfH), rescues both types of stalled ribosomes described above. Our in vitro biochemical assays demonstrate that Cg PrfH hydrolyzes the peptides attached to P-site tRNAs when in complex with both the damaged and intact ribosomes. Two cryo-EM structures of Cg PrfH in complex with the damaged and intact 70S ribosomes revealed that Cg PrfH employs two different regions of the protein to recognize two different stalled ribosomes to orient the GGQ motif for peptide hydrolysis. Thus, using a combination of bioinformatic, biochemical, and structural characterization described here, we have uncovered a family of ribosome rescue factors that possesses dual activities to resolve two distinct stalled protein translation in bacteria.

Isolation of a Unique Monoterpene Diperoxy Dimer From Ziziphora clinopodioides subsp. bungeana Together With Triterpenes With Antidiabetic Properties.

Ziziphora clinopodioides subsp. bungeana (Juz.) Rech.f. is used in traditional medicine for various purposes. Previous phytochemical studies focused on phenolic compounds, but triterpenoids were almost overlooked. The study focused on the isolation of compounds with dual antidiabetic activity from the aerial parts of Z. clinopodioides subsp. bungeana. Separation of CHCl3-soluble fraction by silica gel column chromatography using different mobile phases and purification of compounds by semi-preparative HPLC or preparative TLC. The structures of pure compounds were elucidated by 1D and 2D NMR experiments along with HRMS. Compound 1 was additionally identified by the single crystal X-ray diffraction method. α-Glucosidase inhibitory assay and GLUT4 expression and translocation in C2C12 myotubes were conducted to evaluate antidiabetic potential of isolated compounds. This phytochemical study led to the isolation of 20 compounds, including a unique monoterpene diperoxy dimer (1). Compounds 7 and 9-11 displayed more potent α-glucosidase inhibitory activity (IC50 45.3-135.3 μM) than acarbose used as a positive control (IC50 264.7 μM), while only pomolic acid (5) increased GLUT4 translocation in C2C12 myotubes in a significant manner. Extensive chromatographic separation led to the isolation and identification of a unique monoterpene diperoxy dimer (1) from aerial parts of Z. clinopodioides subsp. bungeana. Some triterpenes inhibited α-glucosidase, another increased GLUT4 translocation. Although none of the isolated compounds demonstrated dual antidiabetic activity, selected triterpenes proved to be potent antidiabetic agents in vitro.

Semisynthesis of Glycosmis pentaphylla Alkaloid Derivatives: Pyranoacridone-Hydroxamic Acid Cytotoxic Conjugates with HDAC and Topoisomerase II α Dual Inhibitory Activity.

Inspired by our previous efforts in the semisynthetic modification of naturally occurring pyranoacridones, we report the targeted design and semisynthesis of dual inhibitors of HDAC and topoisomerase II α (Topo II α) derived from Glycosmis pentaphylla des-N-methylacronycine (1) and noracronycine (8) pyranoacridone alkaloids. Designed from the clinically approved SAHA, the cytotoxic pyranoacridone nuclei from the alkaloids served as the capping group, while a hydroxamic acid moiety functioned as the zinc-binding group. Out of 16 compounds evaluated in an in vitro cytotoxicity assay, KT32 (10c) with noracronycine (8) as the capping group and five-carbon linker hydroxamic acid side chains showed good cytotoxic activity with IC50 values of 1.0, 1.5, and 0.3 μM on MCF-7, CALU-3, and SCC-25 cell lines, respectively. KT32 (10c) showed potent HDAC inhibitory activity and partial Topo II α inhibitory activity in both enzyme assays. The SAR results strongly aligned with the predicted binding affinities from the molecular docking study. KT32 (10c) was further explored for a preliminary mechanistic understanding of SCC-25 cell lines. Flow cytometry analysis suggests that KT32 (10c) induces cell death through apoptosis, as evidenced by the substantial increase in the population of late apoptotic cells.

Co-activating STING-TLR9 pathways promotes radiotherapy-induced cancer vaccination.

Vaccination may cure cancer patients by inducing tumor-specific immune responses. Radiotherapy is an appealing strategy to generate cancer vaccines in situ; thus far, however, only modest and short-lived immune responses are achieved. We here show that radiation combined with co-activating STING-TLR9 can generate powerful in situ cancer vaccines. Notably, radiation at a dose of 12Gy is found to be optimal for boosting tumor cell immunogenicity, and STING-TLR9 co-stimulation by a dual immune activation nano-agonist overrides key immunosuppressive effects associated with radiotherapy. Local radiotherapy combined with the dual immune activation nano-agonists elicits strong systemic anti-tumor immune responses, resulting in complete regression of tumors and metastases in multiple syngeneic murine tumor models. This work introduces a novel and highly potent cancer immunotherapeutic strategy that holds promise for the personalized treatment of intractable cancers.

Triplet Harvesting in Trifluoromethyl Quinoxaline Derivatives via TADF and RTP Mechanisms

In this study, we explore the impact of donor strength on the photophysical properties of novel trifluoromethyl quinoxaline derivatives, which incorporate various electron-donating moieties exhibiting distinct conformational characteristics. The triplet harvesting mechanisms within these quinoxaline systems are facilitated through thermally activated delayed fluorescence (TADF) and room-temperature phosphorescence (RTP), both of which can be modulated by subtle structural alterations in the donor unit. The derivatives demonstrate varying photophysical properties, including pure RTP activity, dual activity (exhibiting both TADF and RTP), and pure TADF, contingent upon the nature of the electron-donating moieties employed. Notably, the intersystem crossing (ISC) rates are significantly higher than the rates of radiative decay, leading to diminished fluorescence quantum yields (ΦDF) of the compounds in toluene solutions. However, embedding the TADF compounds within a rigid polystyrene (PS) matrix results in a remarkable enhancement of ΦDF due to significant reduction of nonradiative pathways related to intramolecular twisting. A considerable conformational disorder of the polymer doped films was observed resulting in non-exponential fluorescence decay and significant shifts of prompt and delayed fluorescence in time-resolved spectra.

Bimetallic doped carbon dot nanozymes for enhanced sonodynamic and nanocatalytic therapy.

Conventional inorganic semiconductors are not suitable for acting as nanozymes or sonosensitizers for in vivo therapeutic nanomedicine owing to the lack of excellent biocompatibility. Biocompatible carbon dots (CDs) exhibit a variety of biological activities due to their adjustable size and surface chemical modification; however, the simultaneous sonodynamic activity and multiple enzyme-mimicking catalytic activity of a single CD have not been reported. Herein, we report the development of bimetallic doped CDs as a high-efficiency nanozyme and sonosensitizer for enhanced sonodynamic therapy (SDT) and nanocatalytic therapy (NCT). By selecting metal-organic complexes like EDTA-FeNa as the carbon source, we ensure that the coordination environments of metal atoms are preserved throughout the low-temperature calcination process. Compared with the single metal doped CDs including Fe-CDs or Ni-CDs, the obtained Fe and Ni co-doped CDs (Fe-Ni-CDs) not only exhibit enhanced sonodynamic activity owing to the decreased bandgap, but also possess augmented dual enzyme-mimicking catalytic activities due to the synergistic effect of bimetallic ions. The Fe-Ni-CD-mediated cascade amplification of ROS generation could lead to the production of 1O2 and O2˙- through SDT, the generation of ˙OH through POD-mimicking catalytic activity, and the provision of more O2 for SDT through CAT-mimicking catalytic activity. Through the integrated multifunctionality of Fe-Ni-CDs, we successfully enhanced the effectiveness of antitumor treatment with a single drug injection and a single US irradiation for enhanced SDT and NCT. This work provides a distinct paradigm of endowing CDs with sonodynamic and multiple enzyme-mimicking catalytic activities for enhanced SDT and NCT through bimetallic ion doping.

Free reactive oxygen species-independent dual enzymatic activity of iron single-atom catalyst for hydrogel-assisted portable visual analysis

Free reactive oxygen species-independent dual enzymatic activity of iron single-atom catalyst for hydrogel-assisted portable visual analysis

Sulphonyl thiourea compounds containing pyrimidine as dual inhibitors of I, II, IX, and XII carbonic anhydrases and cancer cell lines: synthesis, characterization and in silico studies.

Some novel sulphonyl thiourea derivatives (7a-m) containing 4,6-diarylpyrimidine rings were designed and synthesized using a one-pot procedure. These compounds exhibited remarkable dual inhibitory activity against human carbonic anhydrase hCA I, hCA II, hCA IX, and XII isoenzymes and some cancer cell lines. Among them, some thioureas had significantly more potent inhibitory activities in the order of 7l > 7c > 7f (against the hCA I isoform), 7f > 7b > 7c (against the hCA II isoform), 7c > 7g > 7a > 7b (against the hCA IX isoform), and 7d > 7c > 7g > 7f (against the hCA XII isoform). The obtained inhibitory activity data against the hCA IX and XII isoforms showed that compound 7c was the most potent inhibitor in this sulphonyl thiourea series against enzyme hCA IX, with K I = 125.1 ± 12.4 nM, while compound 7d was the most potent inhibitor against enzyme hCA XII, with K I = 111.0 ± 12.3 nM. Compound 7c exhibited strong inhibitory activity among all four tested hCA enzymes, while thiourea 7f was a potent inhibitor for enzymes hCA I, II and XII. All these compounds demonstrated non-competitive inhibition of both enzymes. Some selected potential inhibitory compounds, including 7c, 7d, and 7g, exhibited remarkable cytotoxic activity against human cancer cell lines, including human breast adenocarcinoma (MCF-7), human liver adenocarcinoma (HepG2), human cervical epithelial carcinoma (HeLa), and human lung adenocarcinoma cells (A549). These compounds exhibited low cytotoxicity in the WI-38 cell line. The compounds 7c and 7d were the most potent inhibitors against tumour-associated hCA IX and hCA XII isoenzymes. Furthermore, these compounds exhibited remarkable inhibition against some cancer cell lines, such as MCF-7, HepG2, HeLa, and A549. They were subjected to in silico screening for molecular docking and molecular dynamics simulations. The results of in vitro and in silico studies revealed that compounds 7c and 7d were the most promising derivatives in this series owing to their significant effects on the studied hCA IX and hCA XII isoenzymes, respectively. The results showed that the sulphonyl thiourea moiety was deeply accommodated in the active site and interacted with zinc ions in the receptors.

In situ pyrolysis of ZIF-67 with cobalt nitrate etching for the catalytic oxidation of methane: promoting surface lattice oxygen and molecular oxygen activation

Etching strategy promoted dual activation of surface lattice oxygen and molecular oxygen. The activation of molecular oxygen was the key factor for catalyst performance enhancement.

BMY 7378, a selective α1D-adrenoceptor antagonist, is a new angiotensin converting enzyme inhibitor: In silico, in vitro and in vivo approach

BMY 7378 is a multitarget drug primarily known for its selective antagonism of α1D-adrenoceptors (α1D-AR), exhibiting both hypotensive effects and the ability to prevent or reverse angiotensin II-induced vascular hypertrophy. Notably, BMY 7378 contains a phenylpiperazine moiety, a structural feature associated with angiotensin-converting enzyme (ACE) inhibition. This study aimed to investigate ACE inhibition as a potential pharmacological mechanism of BMY 7378. Using an in silico approach we predicted BMY 7378 interactions with the ACE active site, followed by in vitro activity assays. Additionally, ACE protein expression in the heart was analyzed following four weeks of BMY 7378 treatment in 7–8-month-old spontaneously hypertensive rats (SHR). All assays were benchmarked against captopril, a standard ACE inhibitor. In silico results showed that BMY 7378 binds to the ACE active site, though with reduced interaction with Zn701 (73.7 % compared to captopril), likely due to the pKa of its amino group. The inhibitory concentration 50 (IC50) for BMY 7378 was 136 μM, lower than other reported phenylpiperazine derivatives. Furthermore, BMY 7378 significantly increased ACE expression in the hearts of SHR, with an increase of 8.5-fold compared to captopril. In conclusion, BMY 7378 exhibits dual activity as an α1D-AR antagonist and an ACE inhibitor, making it a promising pharmacological tool for investigating and potentially treating hypertension and its associated cardiovascular complications.

Ru single atoms in Mn2O3 efficiently promote the catalytic oxidation of 5-hydroxymethylfurfural through dual activation of lattice and molecular oxygen

Ru single atoms in Mn2O3 efficiently promote the catalytic oxidation of 5-hydroxymethylfurfural through dual activation of lattice and molecular oxygen