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Rhein, as a plant antibiotic, demonstrates a broad spectrum of pharmacological effects. Nevertheless, its limited water solubility, low bioavailability, and potential hepatotoxicity and nephrotoxicity making it difficult to directly become a medicine, thereby imposing significant constraints on its clinical application. In recent decades, extensive researches have been proceeded on the multifaceted structural modifications of rhein, resulting in notable improvements on pharmacological activities and druggabilities. This review offers a comprehensive overview and advanced update on the biological potential and structural-activity relationships (SARs) of various rhein derivatives, delineating the sites of structural modification and corresponding activity trends of rhein derivatives for future.

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Pharmacological activation of the immunogenic cell death (ICD) pathway by endoplasmic reticulum (ER) targeted photosensitizer (PS) has become a promising strategy for tumor immunotherapy. Despite a clear demand for ER-targeted PS, the sluggish intersystem crossing (ISC) process, unstable excited state, insufficient ROS production, and immunosuppressive tumor microenvironment (ITME) combined to cause the high-efficiency agents are still limited. Herein, three groups commonly used in thermally activated delayed fluorescence (TADF) molecular design are used to modify the excited state characteristics of xanthene-based cyanine PS (obtained the XCy-based PS). The electronic and geometric modulation effectively optimize the excited state characteristics, facilitating the ISC process and prolonging the excited state life for boosting ROS generation. Among them, car-XCy showed 100 times longer excited state life and 225% higher ROS yield than that of original XCy. The satisfactory ROS production and ER-targeted ability of car-XCy arouse intense ER stress to activate the ICD. Adequate antigen presentation promotes the dendritic cell maturation and infiltration of cytotoxic T lymphocytes (CTLs), ultimately reversing the ITME to realize efficient immunotherapy. As a result, significant inhibition is observed in both primary and distant tumors, underscoring the efficacy of this TADF-guiding excited state characteristics modulation strategy for developing photodynamic immunotherapy drugs.

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Heterostructures and the introduction of heterogeneous elements have been regarded as effective strategies to promote electrochemical performance. Herein, sulfur species are introduced by a simple hydrothermal vulcanization method, which constructs the open heterostructure Fe7S8/Mn(OH)2 as a bifunctional material. The open cordyceps-like morphology can make the material contact more sufficiently with the electrolyte, exposing a large number of reaction sites. Furthermore, the introduction of the heterogeneous element S successfully constructs a heterogeneous interface, the interface-modulated composite material consists of Mn atoms contributing the main density of states (DOS) near the Fermi energy level from the density functional theory (DFT) calculations, which optimizes the adsorption energy of oxygen-containing intermediates during the oxygen evolution reaction (OER) process and reduces the reaction energy barrier, being conducive to the improvement of the material's electrochemical properties. As predicted, the Fe7S8/Mn(OH)2 material exhibits remarkable electrochemical properties, such as an overpotential of 202 mV at 10 mA cm-2 for the oxygen evolution reaction and even a specific capacitance of 2198 F g-1 at 1 A g-1. This work provides new insights into the role of introducing sulfur species and controlling the structure of the material, and exemplifies novel design ideas for developing bifunctional materials for energy storage and conversion.

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The strategic design of catalysts for the oxygen evolution reaction (OER) is crucial in tackling the substantial energy demands associated with hydrogen production in electrolytic water splitting. Despite extensive research on birnessite (δ-MnO2) manganese oxides to enhance catalytic activity by modulating Mn3+ species, the ongoing challenge is to simultaneously stabilize Mn3+ while improving overall activity. Herein, oxygen (O) vacancies and nitrogen (N) doping have been simultaneously introduced into the MnO2 through a simple nitrogen plasma approach, resulting in efficient OER performance. The optimized N-MnO2v electrocatalyst exhibits outstanding OER activity in alkaline electrolyte, reducing the overpotential by nearly 160 mV compared to pure pristine MnO2 (from 476 to 312 mV) at 10 mA cm-2, and a small Tafel slope of 89 mV dec-1. Moreover, it demonstrates excellent durability over a 122 h stability test. The introduction of O vacancies and incorporation of N not only fine-tune the electronic structure of MnO2, increasing the Mn3+ content to enhance overall activity, but also play a crucial role in stabilizing Mn3+, thereby leading to exceptional stability over time. Subsequently, density functional theory calculations validate the optimized electronic structure of MnO2 achieved through the two engineering methods, effectively lowering the intermediate adsorption free energy barrier. Our synergistic approach, utilizing nitrogen plasma treatment, opens a pathway to concurrently enhance the activity and stability of OER electrocatalysts, applicable not only to Mn-based but also to other transition metal oxides.

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When designing live-attenuated respiratory syncytial virus (RSV) vaccine candidates, attenuating mutations can be developed through biologic selection or reverse-genetic manipulation and may include point mutations, codon and gene deletions, and genome rearrangements. Attenuation typically involves the reduction in virus replication, due to direct effects on viral structural and replicative machinery or viral factors that antagonize host defense or cause disease. However, attenuation must balance reduced replication and immunogenic antigen expression. In the present study, we explored a new approach in order to discover attenuating mutations. Specifically, we used protein structure modeling and computational methods to identify amino acid substitutions in the RSV nonstructural protein 1 (NS1) predicted to cause various levels of structural perturbation. Twelve different mutations predicted to alter the NS1 protein structure were introduced into infectious virus and analyzed in cell culture for effects on viral mRNA and protein expression, interferon and cytokine expression, and caspase activation. We found the use of structure-based machine learning to predict amino acid substitutions that reduce the thermodynamic stability of NS1 resulted in various levels of loss of NS1 function, exemplified by effects including reduced multi-cycle viral replication in cells competent for type I interferon, reduced expression of viral mRNAs and proteins, and increased interferon and apoptosis responses.

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Natural products with antibacterial activity are highly desired globally to combat against multidrug-resistant (MDR) bacteria. Antibacterial peptide (ABP), especially cyclic ABP (CABP), is one of the abundant classes. Most of them were isolated from microbes, demonstrating excellent bactericidal effects. With the improved proteolytic stability, CABPs are normally considered to have better druggability than linear peptides. However, most clinically-used CABP-based antibiotics, such as colistin, also face the challenges of drug resistance soon after they reached the market, urgently requiring the development of next-generation succedaneums. We present here a detail review on the novel naturally-occurring CABPs discovered in the past decade and some of them are under clinical trials, exhibiting anticipated application potential. According to their chemical structures, they were broadly classified into five groups, including (i) lactam/lactone-based CABPs, (ii) cyclic lipopeptides, (iii) glycopeptides, (iv) cyclic sulfur-rich peptides and (v) multiple-modified CABPs. Their chemical structures, antibacterial spectrums and proposed mechanisms are discussed. Moreover, engineered analogs of these novel CABPs are also summarized to preliminarily analyze their structure-activity relationship. This review aims to provide a global perspective on research and development of novel CABPs to highlight the effectiveness of derivatives design in identifying promising antibacterial agents. Further research efforts in this area are believed to play important roles in fighting against the multidrug-resistance crisis.

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Light-driven water splitting has gained increasing attention as an eco-friendly method for hydrogen production. There is a pressing need to enhance the performance of catalysts for the commercial viability of this reaction. Many methods have been proposed to improve catalyst performance; however, an economical and straightforward approach remains a priority. This paper presents an uncomplicated technique called acid treatment, which augments the catalytic performance of nanoparticles. The method promotes a change in the catalytic reactivity by causing a deficit in electron density of Ti and O on the surface of TiO2 nanoparticles without altering their size, morphology, or crystal structure. In the Eosin Y sensitized photocatalytic hydrogen production system, nitric acid treated TiO2 (16.95 µmol/g) exhibited 1.5 times the hydrogen production compared to bare TiO2 (11.15 µmol/g).

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Background: Histone deacetylase inhibitors (HDACIs) are important as anticancer agents. Objective: This study aimed to investigate some key structural features of HDACIs via the design, synthesis and biological evaluation of novel benzamide-based derivatives. Methods: Novel structures, designed using a molecular modification approach, were synthesized and biologically evaluated. Results: The results indicated that a subset of molecules with CH3/NH2 at R2 position possess selective antiproliferative activity. However, only those with an NH2 group showed HDACI activity. Importantly, the shorter the molecule length, the stronger HDACI. Among all, 7j was the most potent HDAC1-3 inhibitor and antiproliferative compound. Conclusion: The results of the present investigation could provide valuable structural knowledge applicable for the development of the HDACIs and benzamide-based antiproliferative agents in the future.

[Box: see text].

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Through bioassay-guided isolation, eight undescribed coumarins (1-8), along with six reported coumarins (9-14), were obtained from Coriaria nepalensis. The new structures were determined by using IR, UV, NMR, HRESIMS, and ECD calculations. The results of the biological activity assays showed that compound 9 exhibited broad spectrum antifungal activities against all tested fungi in vitro and a significant inhibitory effect on Phytophthora nicotianae with an EC50 value of 3.00 µg/mL. Notably, compound 9 demonstrated greater curative and protective effects against tobacco balack shank than those of osthol in vivo. Thus, 9 was structurally modified to obtain new promising antifungal agents, and the novel derivatives (17b, 17j, and 17k) exhibited better effects on Sclerotinia sclerotiorum than did lead compound 9. Preliminary mechanistic exploration illustrated that 9 could enhance cell membrane permeability, destroy the morphology and ultrastructure of cells, and reduce the exopolysaccharide content of P. nicotianae mycelia. Furthermore, the cytotoxicity results revealed that compound 9 exhibited relatively low cytotoxicity against HEK293 cell lines with an inhibition rate of 33.54% at 30 µg/mL. This research is promising for the discovery of new fungicides from natural coumarins with satisfactory ecological compatibility.

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Several flavonoids have been shown to exert anti-osteoporosis activity. However, the structure-activity relationship and the mechanism of anti-osteoporosis activity of flavonoids remain unknown. In this study, we prepared a series of novel homoisoflavonoid (HIF) derivatives to evaluate their inhibitory effects on osteoclastogenesis using TRAP-activity in vitro assay. Then, the preliminary structure-activity relationship was studied. Among the evaluated novel flavonoids, derivative 5g exerted the most inhibitory bioactivity on primary osteoclast differentiation without interfering with osteogenesis. It was hence selected for further in vitro, in vivo and mechanism of action investigation. Results show that 5g likely directly binds to the fibroblast growth factor receptor 1 (FGFR1), decreasing the activation of ERK1/2 and IκBα/NF-κB signaling pathways, which in turn blocks osteoclastogenesis in vitro and osteoclastic bone loss in vivo. Our study shows that homoisoflavonoid (HIF) derivatives 5g can serve as a potential novel candidate for treating osteoporosis via inhibition of FGFR1.

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Low-temperature (9-12 °C) pulsed electric field (PEF) was investigated in milk before cream separation at different intensities (9-27 kV/cm, 66 µs, 16-28 kJ/L) regarding its potential to render processing more sustainable, retain a high physico-chemical quality, enhance functional properties, and gently modify the structure of the milk fat globule membrane (MFGM). Cream volume per L milk were most efficiently increased by 31 % at the lowest PEF intensity in comparison to untreated milk and cream (P < 0.05). Untreated and PEF-treated milk and obtained cream were assessed with compositional (fat, protein, casein, lactose, and total solids content) and particle size distribution analyses, showing no significant differences (P ≥ 0.05) and, thus, indicating retention of 'native-like' product quality. Overrun and stability of cream, whipped for 20 and 60 s at 15000 rpm using a high-shear mixer, were improved most notably by the lowest and the highest PEF intensities, achieving up to 69 % enlarged overrun and up to 22 % higher stability, respectively (P < 0.05), than in untreated whipped cream. Protein component analyses for milk and cream were carried out by sodium dodecylsulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Noticeable differences between untreated and PEF-treated milk were not observed, but the SDS-PAGE results for cream showed noticeably different bands for some of the protein components, indicating structural changes in MFGM-, whey-, and phospho-proteins due to PEF and/or separator processing effects. More intense bands of xanthine oxidase, xanthine dehydrogenase, butyrophilin, bovine serum albumine, adipophilin (ADPH), and glycoproteins PAS6/7 were observed specifically at 21 kV/cm. Gentle electroporation of both MFGM layers by PEF was determined based on the changes in MFGM monolayer components, such as ADPH and PAS 6/7, exhibiting intensified bands. PEF intensity-dependent impact on the structure of MFGM and casein, leading to a reconfiguration of the cream matrix due to different structuring interactions among proteins, among milk fat globules, and between fat and protein components, was suggested. Overall, low-temperature PEF applied at different intensities showed great potential for gentle, efficient, and functional properties-tailored dairy processing and may also enable effective extraction of highly bioactive ingredients from dairy sources.

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Fine-tuning nanoscale structures, morphologies, and electronic states are crucial for creating efficient water-splitting electrocatalysts. In this study, a method for electronic structure engineering to enhance overall water splitting in a corrosion-resistant electrocatalyst matrix by integrating Pt, P dual-doped Ni4Mo electrocatalysts onto a Ti4O7 nanorod grown on carbon cloth (Pt, P-Ni4Mo-Ti4O7/CC) is introduced. By optimizing platinum and phosphorus concentrations to 1.18% and 2.42%, respectively, low overpotentials are achieved remarkably: 24 mV at 10 mA cm-2 for the hydrogen evolution reaction and 290 mV at 20 mA cm-2 for the oxygen evolution reaction in 1.0 m KOH. These values approach or surpass those of benchmark Pt-C and IrO2 catalysts. Additionally, the Pt, P-Ni4Mo-Ti4O7/CC bifunctional electrocatalyst displays low cell potentials across various mediums, maintaining excellent current retention (96% stability after 40 h in mimic seawater at 20 mA cm-2) and demonstrating strong corrosion resistance and suitability for seawater  electrolysis. As a cathode in magnesium/seawater batteries, it achieves a power density of 7.2 mW cm-2 and maintains stability for 100 h. Density functional theory simulations confirm that P, Pt doping-assisted electronic structure modifications augment electrical conductivity and active sites in the hybrid electrocatalysts.

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BACKGROUND: FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated gene in acute myeloid leukemia. As a receptor tyrosine kinase (RTK), FLT3 plays a role in the proliferation and differentiation of hematopoietic stem cells. As the most frequent molecular alteration in AML, FLT3 has drawn the attention of many researchers, and a lot of small molecule inhibitors targeting FLT3 have been intensively investigated as potential drugs for AML therapy. METHODS: In this paper, PubMed and SciFinder® were used as a tool; the publications about "FLT3 inhibitor" and "Acute myeloid leukemia" were surveyed from 2014 to the present with an exclusion of those published as patents. RESULTS: In this study, the structural characterization and biological activities of representative FLT3 inhibitors were summarized. The major challenges and future directions for further research are discussed. CONCLUSION: Recently, numerous FLT3 inhibitors have been discovered and employed in FLT3-mutated AML treatment. In order to overcome the drug resistance caused by FLT3 mutations, screening multitargets FLT3 inhibitors has become the main research direction. In addition, the emergence of irreversible FLT3 inhibitors also provides new ideas for discovering new FLT3 inhibitors.

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Orthosiphon aristatus is a well-known folkloric medicine and herb for Guangdong soup for the treatment of rheumatism in China. Eight isopimarane-type and migrated pimarane-type diterpenoids (1-8), including a new one with a rarely occurring α,ß-unsaturated diketone C-ring, were isolated from O. aristatus. Their structures were determined by spectroscopic methods and quantum chemical calculations. Furthermore, the most abundant compound, orthosiphol K, was structurally modified by modern synthetic techniques to give seven new derivatives (9-15). The anti-rheumatoid arthritis activity of these diterpenoids were evaluated on a TNF-α induced MH7A human rheumatoid fibroblast-like synoviocyte model. Compound 10 showed the most potent activity among these compounds. Based on their inhibitory effects on the release levels of IL-1ß, the preliminary structure-activity relationships were concluded. Furthermore, western blot analysis revealed that 10 could increase the expression of IκBα and decrease the expression of NF-κB p65, and the expression levels of COX-2 and NLRP3 proteins were consequently down-regulated.

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Rotenone is a naturally occurring compound shown to exhibit antiproliferative activity against various cancer cell lines, indicating its potential as a lead anticancer agent. However, its toxicity against normal cells has prompted further investigation and chemical modifications. In this study, a library of carbonyl group-modified rotenone derivatives was synthesized and evaluated for their antiproliferative activities against MCF-7 breast cancer cells, A549 human lung carcinoma cells, and HCT116 human colorectal cancer cells using 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. The results showed several promising compounds that inhibited cell proliferation. Specifically, the oxime and alcohol rotenone derivatives exhibited antiproliferative activities against all 3 cancer cell lines, while the ethoxy, carbamate, and alkene derivatives are selective against MCF-7 (IC50 =5.72 µM), HCT116 (IC50 =8.86 µM), and A549 (IC50 =0.11 µM), respectively. SwissADME analysis showed that the physicochemical properties and drug-likeness of the synthesized rotenone derivatives were within the set limits, suggesting the favorable characteristics of these compounds for drug development. The findings obtained in this work highlight the potential of rotenone derivatives as promising chemotherapeutic candidates.

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Peptides, as potential therapeutics continue to gain importance in the search for active substances for the treatment of numerous human diseases, some of which are, to this day, incurable. As potential therapeutic drugs, peptides have many favorable chemical and pharmacological properties, starting with their great diversity, through their high affinity for binding to all sort of natural receptors, and ending with the various pathways of their breakdown, which produces nothing but amino acids that are nontoxic to the body. Despite these and other advantages, however, they also have their pitfalls. One of these disadvantages is the very low stability of natural peptides. They have a short half-life and tend to be cleared from the organism very quickly. Their instability in the gastrointestinal tract, makes it impossible to administer peptidic drugs orally. To achieve the best pharmacologic effect, it is desirable to look for ways of modifying peptides that enable the use of these substances as pharmaceuticals. There are many ways to modify peptides. Herein we summarize the approaches that are currently in use, including lipidization, PEGylation, glycosylation and others, focusing on lipidization. We describe how individual types of lipidization are achieved and describe their advantages and drawbacks. Peptide modifications are performed with the goal of reaching a longer half-life, reducing immunogenicity and improving bioavailability. In the case of neuropeptides, lipidization aids their activity in the central nervous system after the peripheral administration. At the end of our review, we summarize all lipidized peptide-based drugs that are currently on the market.

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Erianin, a bioactive compound extracted from Dendrobium, a traditional Chinese medicine, exhibits remarkable anti-cancer properties through diverse molecular mechanisms and has attracted the attention of medicinal chemists. However, the low solubility in water, rapid metabolism and elimination from the body lead to poor bioavailability of Erianin, and greatly hinder its clinical application. The development of new Erianin derivatives is continuously proceed to improve its anticancer effects. In recent years, although important progress in the development of Erianin and the publication of some reviews in this aspect, the mechanism against various cancers, pharmacokinetic study, structural modification as well as structure-activity relationships have not been thoroughly considered. This review is aimed at providing complete picture regarding the above aspects by reviewing studies from 2000 to 2023.06. This review also supplies some important viewpoints on the design and future directions for the development of Erianin derivatives as possible clinically effective anticancer agents.

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Fusaricidin, a lipopeptide antibiotic, is specifically produced by Paenibacillus polymyxa strains, which could strongly inhibit Fusarium species fungi. Fusaricidin bio-synthetase A (FusA) is composed of six modules and is essential for synthesizing the peptide moiety of fusaricidin. In this study, we confirmed the FusA of Paenibacillus polymyxa strain WLY78 involved in producing Fusaricidin LI-F07a. We constructed six engineered strains by deletion of each module within FusA from the genome of strain WLY78. One of the engineered strains is able to produce a novel compound that exhibits better antifungal activity than that of fusaricidin LI-F07a. This new compound, known as fusaricidin [ΔAla6] LI-F07a, has a molecular weight of 858. Our findings reveal that it exhibits a remarkable 1-fold increase in antifungal activity compared to previous fusaricidin, and the fermentation yield reaches ~55 mg/L. This research holds promising implications for plant protection against infections caused by Fusarium and Botrytis pathogen infection.

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Abnormal osteoclast differentiation causes various bone disorders such as osteoporosis. Targeting the formation and activation of osteoclasts has been recognized as an effective approach for preventing osteoporosis. Herein, we synthesized eleven 2-NMPA derivatives which are (2-(2-chlorophenoxy)-N-(4-alkoxy-2-morpholinophenyl) acetamides, and evaluated their suppression effects on osteoclastogenesis in vitro by using TRAP-staining assay. Among the synthesized eleven novel 2-NMPAs, 4-(2-(2-chlorophenoxy)acetamido)-3-morpholinophenyl trifluoromethanesulfonate (11b), 4-(2-(2-chlorophenoxy) acetamido)-3-morpholinophenyl-3-(N-(2-oxo-2-((2-(phenylthio) phenyl) amino) ethyl)methylsulfonamido)benzoate (11d), and 4-(2-(2-chlorophenoxy) acetamido)-3-morpholinophenyl 4-acetamidobenzenesulfonate (11h) displayed highly inhibitory bioactivity on the differentiation of primary osteoclasts. 11h was selected for further investigation of the inhibitory effects and potential mechanism involved in the suppression of osteoclastogenesis. In vitro analysis suggested that 11h inhibited osteoclastogenesis with an IC50 of 358.29 nM, decreased the formation of F-action belts and bone resorption, without interfering cell viability and osteoblast differentiation. Furthermore, the mRNA expressions of osteoclast-specific genes such as Acp5, Nfatc1, Dc-stamp, Atp6v0d2, Mmp9, and Ctsk significantly decreased following 11h treatment. RANKL-induced osteoclast-specific proteins analysis demonstrated that 11h suppressed osteoclast differentiation by downregulating of RANKL-mediated TRAF6 expression, followed by inactivation of PI3K/AKT and IκBα/NF-κB signaling pathways. Finally, 11h inhibited ovariectomy-induced bone loss in vivo. Therefore, the current work highlighted the therapeutic potential of 11h as an anti-osteoporosis lead compound.

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The aim of this study was to produce sustained-release tablets by V-shaped blending of polymer and tablets without using solvents or heating, and we investigated the design of polymer particles with high coating performance by modifying the structure of the particles using sodium lauryl sulfate. Dry-latex particles of ammonioalkyl methacrylate copolymer were prepared by adding the surfactant into aqueous latex, followed by freeze drying. The resulting dry latex was mixed with tablets (1:10) using a blender and the resulting coated tablets were characterized. Tablet coating by the dry latex was promoted as the weight ratio of surfactant to polymer increased. At a surfactant ratio of 5%, deposition of the dry latex was most effective and the resulting coated tablets (annealed at 60 °C/75%RH for 6 h) exhibited sustained-release characteristics over a period of 2 h. The addition of SLS prevented coagulation of colloidal polymer in the freeze drying, resulting in a loose-structured dry latex. This latex was easily pulverized by V-shaped blending with tablets and the resulting fine particles with high adhesiveness were deposited on the tablets. However, at a surfactant ratio of 10%, the coating of dry latex decreased due to reduced adhesiveness.

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