Narcolepsy severely impairs quality of life, characterized by irresistible sleepiness and persistent fatigue. The first-line agent modafinil (MOD) promotes wakefulness primarily by inhibiting the dopamine transporter (DAT), thereby elevating synaptic dopamine levels. In parallel, positive allosteric modulators (PAMs) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor enhance glutamatergic transmission, demonstrating notable wakefulness-promoting and anti-fatigue potential. Using MOD as a lead compound and leveraging the crystal structure of the AMPA receptor together with a homology model of the dopamine transporter (DAT), we designed, optimized and synthesized a series of diphenylmethyl-sulfinyl-bridged bisamide derivatives. Their activities were evaluated in vivo, identifying compound B1 as the most promising candidate. B1 significantly prolonged sleep latency and reduced sleep duration in pentobarbital-induced sleep models without increasing spontaneous locomotion. It also extended forced swimming time and rotarod endurance. Furthermore, B1 alleviated behavioral deficits from acute sleep deprivation. Preliminary mechanistic studies indicated that B1 exhibits moderate affinity for the dopamine transporter and enhances AMPA receptor-mediated ion currents while delaying channel deactivation, thereby functioning as a positive allosteric modulator. In summary, B1 is a novel and potent wakefulness-promoting and anti-fatigue candidate, supporting its further development as a therapeutic agent for narcolepsy and fatigue-related conditions.

Aiming to develop safe and efficient cognitive enhancers, this study reports the design, synthesis, and biological evaluation of novel α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor modulators derived from the lead compound CX717. Twenty-four derivatives were designed, synthesized, and characterized by 1H-NMR, 13C-NMR, and high resolution MS (HR-MS). Molecular docking studies indicated that, compared to CX717, the compounds exhibited lower binding energy to the AMPA receptor. Cognition-improved activity was evaluated by passive avoidance, active avoidance, novel object recognition, and novel place recognition tests in mice. The results demonstrated that nine compounds significantly enhanced cognitive function in mice, with compounds B7 and C3 showing efficacy superior to CX717 in vivo. Furthermore, B7 and C3 alleviated serum oxidative stress, enhanced hippocampal glutamate transport efficiency, and reduced serum pro-inflammatory cytokine levels in scopolamine-treated mice. Subacute toxicity studies revealed favorable safety profiles for both compounds. Molecular dynamics simulations supported stable binding of B7 and C3 to the AMPA receptor, consistent with the structural modification strategy. Surface plasmon resonance (SPR) analysis demonstrated that B7 and C3 bound directly to the GluR2 protein with moderate affinity, with C3 showing higher affinity than B7. Patch-clamp experiments further showed that B7 and C3 positively modulated AMPA receptor-mediated currents, supporting their positive allosteric modulator (PAM)-like activity. The membrane permeability assay suggested that B7 and C3 had higher passive membrane permeability than CX717 in vitro. In conclusion, B7 and C3 demonstrated superior cognition-improved activity and safety compared to CX717, highlighting their potential as candidates for treating cognitive disorders.

In order to identify promising radioprotector candidates, a series of benzyl sulfoxide/sulfone coumarin derivatives were designed and synthesized based on the reported activity of Ex-Rad. Most of the target compounds demonstrated significant radioprotective effects at concentrations of 40 μmol/L and 20 μmol/L in HUVECs. Among them, compounds 5q and 5u displayed superior activity in mitigating DNA damage compared with Ex-RAD. Notably, compound 5u significantly enhanced the viability of mice exposed to a lethal dose of ionizing radiation. In summary, the above findings suggested that compound 5u might be a promising radioprotective agent deserving further investigation.

Radiation-induced skin injury (RSI) is a common and debilitating complication of radiotherapy, significantly impairing patients' quality of life. High-Mobility Group Box 1 (HMGB1), a key damage-associated molecular pattern (DAMP) protein, plays a critical role in propagating the inflammatory response following radiation exposure. This study aims to discover small molecule compounds that can antagonize and alleviate radiation-induced skin damage through HMGB1. Two novel classes of compounds were designed and synthesized based on molecular docking analysis of Methotrexate (MTX) and rosiglitazone (RSG) binding to HMGB1. The majority of synthesized compounds exhibited low cytotoxicity (IC₅₀ > 80 μM). Among them, 30 emerged as the lead candidate, exhibiting significant radioprotective effects in both HaCaT and JB6 cell lines. In vivo, topical application of 30-loaded hydrogel accelerated wound healing, reduced inflammatory cell infiltration, promoted skin regeneration, and significantly regulateddown the levels of inflammatory factors (HMGB1 and IL-6). Mechanistic studies suggest that 30 may exert its protective effects through the HMGB1-TLR4-NF-κB signaling pathway, while molecular dynamics simulations predicted stable binding of 30 to HMGB1. In conclusion, 30 represents a novel small-molecule HMGB1 inhibitor with significant therapeutic efficacy against RSI, validating HMGB1 as a viable target for the development of radioprotective agents.

Discovering effective anti-inflammatory peptides targeting the NF-κB pathway is a critical research priority. Herein, a docking study was carried out to screen 25 original linear peptides. Next, 44 novel stapled peptides via the all-hydrocarbon cross-linking strategy were designed and synthesized. 75%-80% stapled peptides displayed reduced cytotoxicity and improved anti-inflammatory activity over the original peptides in vitro. Compared with Dex, s-12s significantly inhibited the expression of proinflammatory mediators in vitro and in vivo. Notably, s-12s also protected mice from LPS-induced mortality and acute organ injury. Mechanistically, s-12s reduced LPS-induced activation of the NF-κB pathway. Moreover, surface plasmon resonance and MD simulations have determined the possibility of NF-κB as a target for s-12s. Therefore, s-12s could be used as a promising therapeutic candidate for inflammatory disorders. Meanwhile, these results have proven that the all-hydrocarbon stapling of anti-inflammatory peptides was a feasible approach for the future development of anti-inflammatory therapeutics.

To search for safe and efficient anti-fatigue active molecules, 16 capsaicin (CAP) derivatives were synthesized by replacing the unsaturated carbon-carbon double bond in capsaicin with a rigid benzene ring via condensation, chlorination, and amidation reactions using vanillylamine hydrochloride as the starting material, with yields ranging from 44.1 to 79.1%. Their structures were confirmed by 1H-NMR, 13C-NMR, and MS (electrospray ionization [ESI]). In vitro assays demonstrated that N8 exerted superior transient receptor potential vanilloid 1 (TRPV1) agonistic activity compared to CAP at a concentration of 10 μM, upregulated peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) expression in a concentration-dependent manner (1.25-10 μM), and showed no significant toxicity to C2C12 myotube cells at 0.78-100 μM. In vivo evaluations in mice (15 mg/kg, 31-d gavage) demonstrated that N8 had no adverse effect on body weight but significantly prolonged rotarod duration (143.5%, p < 0.001) and forced swimming time (75.6%, p < 0.001), increased serum lactate dehydrogenase (LDH) levels (p < 0.01), decreased serum urea nitrogen (SUN) levels (p < 0.001) and lactic acid (LA) accumulation (p < 0.001), and elevated hepatic and muscle glycogen contents (p < 0.001) compared with the fatigue control group. Mechanistic studies via Western blot, mitochondrial fluorescence staining, cellular thermal shift assay, and molecular docking revealed that N8 had better binding stability to TRPV1 than CAP (relative binding rate at 65°C: 86.7 vs. 21.5%), activated the TRPV1 channel, synergistically upregulated the expression of cluster of differentiation 36 (CD36), carnitine palmitoyltransferase 1M (CPT1M), SURF1, and cytochrome c1 (CYC1), promoted mitochondrial biogenesis, and optimized muscle energy metabolism. These results indicate that N8 demonstrates superior anti-fatigue activity both in vitro and in vivo compared to CAP, making it a potential candidate for anti-fatigue drug development.

Toll-like receptors (TLRs), a family of pattern recognition receptors of the innate immune system, have been shown to exert radioprotective effects by activating the NF-κB signaling pathway. In this context, we designed and synthesized a series of novel TLR2/1 small molecule agonists, 1H-1,2,3-triazole derivatives, to evaluate their radioprotective activity, with compound H9 exhibiting the most potent radiation-protective effect.H9 showed significant radioprotective effects in mice irradiated with 8.5 Gy of 60Co γ rays. The survival rates of the 80 mg/kg and 60 mg/kg H9-treated groups were both 100%. Furthermore, H9 can accelerate the recovery of peripheral blood cells in irradiated mice. The ELISA experiment showed that the levels of the antiradiation cytokine biomarker G-CSF were significantly increased in the serum of irradiated mice after treatment with H9. In human TLR2 and TLR1 transiently cotransfected HEK 293 T cells., H9 exhibits significant TLR2/1 agonist activity. Immunoprecipitation and cellular thermal shift assays (CETSA) confirmed that H9 targets the TLR2/1 rather than TLR2/6 heterodimeric complex. Summary: We demonstrated that H9 is a novel TLR2/1 agonist with significant efficacy in acute radiation protection, indicating that TLR2/1 small molecule agonists hold broad promise for applications in acute radioprotection.

Using melittin and its bioactive fragment as structural modifiers, we synthesized and characterized a series of analogs incorporating distinct modification patterns. Through nitric oxide production screening, analogs demonstrating anti-inflammatory potential were identified and subsequently evaluated for enzymatic stability, hemolytic activity, and cytotoxicity in vitro . Mechanistic investigations via enzyme-linked immunosorbent assay (ELISA) revealed their anti-inflammatory pathways, which was followed by in vivo validation of therapeutic efficacy. Notably, analogs E1 and S15-1 exhibited optimal pharmacological profiles with minimal hemolysis and potent anti-inflammatory performance. This study demonstrates that strategic structural modifications not only significantly reduce hemolytic activity and cytotoxicity but also preserve anti-inflammatory efficacy at concentrations exceeding melittin’s toxic threshold. Furthermore, the optimized analogs displayed enhanced α-helical content and protease resistance compared to melittin. These findings highlight the critical influence of modification sites and strategies on modulating the therapeutic index, biological stability, and safety profile of melittin-derived peptides.

NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) has a fundamental role in host defense and is involved in diverse inflammatory diseases. NLRP3 protein expression is tightly controlled by the ubiquitin system. In particular, NLRP3 protein degradation has been extensively studied. In contrast, the mechanisms to stabilize NLRP3 protein are much less known. Here, we demonstrated the critical role of ubiquitin-specific protease 13 (USP13) in regulating NLRP3 protein stability and inflammasome activation independently of its deubiquitinating enzyme activity. USP13 competes with E3 ubiquitin ligase TRIM31 to interact with NLRP3 and prevents TRIM31-mediated NLRP3 ubiquitination at K192 and K496 sites, thereby inhibiting proteasomal degradation of NLRP3. USP13 deficiency reduces NLRP3 protein expression in both human and mouse macrophages, which consequently inhibits NLRP3 inflammasome assembly and activation. Accordingly, deficiency of USP13 attenuates monosodium urate crystal-induced mouse peritonitis. Overall, our findings reveal a previously unrecognized regulatory mechanism of NLRP3 stability by USP13 and provide a potential therapeutic target for NLRP3-driven diseases.

To search for safe and efficient anti-hypoxia active molecules, 27 derivatives were synthesized by introducing aminoalkyl groups at daidzein's position-7 and position-8. The structures of these derivatives were confirmed by 1H-NMR, 13C-NMR, and mass spectrometry. The anti-hypoxia activity was evaluated in vitro using a cell hypoxia model established with the AnaeroPack-anaero. The results showed that 9 compounds significantly enhanced cell viability under hypoxic conditions, with compounds 2a, 2b, 4d, 5a, and 5d exhibiting in vitro anti-hypoxia activity significantly superior to daidzein. And the drug-like properties prediction results of the target compounds indicated that compounds 2a, 2b, 4d, 5a, and 5d may also demonstrate favorable pharmacokinetic properties. Further, the anti-hypoxia activity in vivo of these 5 derivatives were evaluated via normobaric hypoxia and hypobaric hypoxia models. The results indicated that all of the 5 compounds extended the survival time of mice under normobaric hypoxia to varying degrees, and they also alleviated oxidative stress damage to the brain and heart of mice under hypobaric hypoxia. Among these, compound 2a demonstrated superior anti-hypoxia activity both in vitro and in vivo compared to daidzein, making it worthy of further study as a potential candidate for an anti-hypoxia drug.

With the development of nuclear technology, the risk of people being exposed to nuclear radiation is increasing. So the development of efficient and safe radiation protection agents for nuclear emergencies is urgent. In this study, a series of novel quinoxaline molecules were designed and synthesized with Ex-RAD and TLR2 agonist as the lead, showing anti-radiation effects and compound Z9 was the best one of them. Our work indicated that Z9 emerged as a potent dual modulator targeting both TLR2 and P53 pathway, remarkably preventing the radiation-induced death in mice with the survival rate of 100 %. In the same time, Z9 had significant radioprotection of the haematopoietic system and intestinal villi in mice. In addition, Z9 significantly reduced radiation-induced apoptosis, DNA damage, P53 and Bax expression of AHH-1, while Z9 up-regulated the expressions of TLR2 downstream proteins MyD88 and P65 of HUVECs. Notably, Z9 showed excellent stability and affinity for the TLR2 protein conjugate in molecular docking and molecular dynamics simulations. These findings suggested that Z9 was worth further research being a potential candidate for anti-radiation drugs, as the dual modulator of P53/TLR2.

3,4-dihydroxybenzenesulfonyl-functionalized polyethyleneimine (PS), a novel polymeric chelator, was synthesized by conjugating 3,4-dihydroxybenzenesulfonyl (CAM) groups with branched polyethyleneimine (BPEI, MW = 600 Da) via N-acylation. PS demonstrated a high uranium adsorption capacity of 78.08% at a concentration of 4 mg/mL, accompanied by significant selectivity over competing ions such as Ca2+, Zn2+, and Cu2+. Notably, in competitive adsorption experiments, PS exhibited a uranium adsorption rate of 59.49%, which was 3.95 times higher than that of calcium (15.06%) in the Ca2+ system. Cytotoxicity assays revealed enhanced biocompatibility (IC50 = 86.98 μg/mL), surpassing CaNa3-DTPA 3.7-fold. In a uranium exposure model (200 μg/mL), PS significantly improved cell survival rates and reduced intracellular uranium levels by 77.37% (immediate administration) and 64.18% (delayed administration). These findings establish PS as a potent and safe polymeric chelator for uranium decorporation, offering a promising strategy for mitigating the hazards of radioactive materials.

Fatigue is a prevalent issue in modern fast-paced lifestyles, exerting numerous adverse effects. Piperonylic acid piperidide (1-BCP), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor modulator, has demonstrated efficacy in alleviating sleep deprivation-induced fatigue. Furthermore, it significantly extends forced swimming time in mice and inhibits fatigue-induced changes in biochemical indices, validating its antifatigue effects. In this paper, a series of small-molecule compounds were designed with 1-BCP as the lead, from which the target compounds were screened by molecular dynamics simulation and molecular docking with the AMPA receptor. The target compounds were synthesised and evaluated for their anti-fatigue activity. The results of in vivo experiments showed that some compounds exhibited better anti-fatigue activity, among which compound A1 demonstrated the most significant activity, surpassing that of 1-BCP. The results of molecular dynamics simulation showed that A1 was able to bind to the AMPA receptor, preliminarily verifying the feasibility of the strategy for structural modification of 1-BCP. Taken together, A1 is a promising modulator of AMPA receptors. It is a potential candidate for further research on anti-fatigue drug development.

Ionizing radiation in space, radiation devices or nuclear disasters are major threats to human health and public security. In this paper, in order to find the potential novel compounds decreasing the radiation-induced damage by targeting p53 apoptosis pathway and TLR2 passway, a series of novel quinoline derivatives were designed, synthesized, and evaluated their biological activities. Most of the synthesized compounds showed significant radioprotective effects in vitro, and the compound 5 has the best performance. Therefore, we verified its radioprotective activity in vivo and investigated the mechanism of its excellent activity. The results in vivo indicated that compound 5 not only markedly enhanced the survival rate (80 %) of mice 30 days after lethal exposure to irradiation, but also significantly reduced the radiation-induced damage to haematopoietic system and intestinal tissue of mice. The mechanistic studies indicated that compound 5 acted on the p53 pathway to reduce radiation-induced cell apoptosis and at the same time stimulated TLR2 to up-regulate the expressions of radiation protection factors. Molecular dynamics study shows that compound 5 would effectively bind to the TLR2 protein and further revealed the binding mechanism. Taken together, all the findings of our study demonstrate the quinoline derivative 5 is a potent radioprotective compound, which holds a great therapeutic potential for further development.

Xanthoceras sorbifolium Bunge, also known as Tu-Mu-Gua and Wen-Dan-Ge-Zi, has several applications. Clinical data and experimental studies have shown anti-tumor, anti-inflammatory, anti-bacterial, and anti-oxidant properties of Xanthoceras sorbifolium Bunge that inhibits prostate hyperplasia, lowers blood pressure and lipid level, and treats enuresis and urinary incontinence. It also has neuroprotective effects and can treat Alzheimer’s disease and Parkinson’s syndrome. The research on the chemical composition and pharmacological effects of Xanthoceras sorbifolium Bunge has been increasing. Triterpenoid and triterpenoid saponins are the main constituents in Xanthoceras sorbifolium Bunge and exhibit biological activities. In this review, we summarized the research progress on triterpenoids and their glycosides in Xanthoceras sorbifolia, including the chemical constituents, pharmacological activities, and biogenic pathways of triterpenoid mother nucleus. The results would provide a reference for further research and development of triterpenoids and their glycosides in Xanthoceras sorbifolia.

Orychophragmus violaceus (L.) O. E. Schulz (Brassicaceae) is widely distributed and plentiful in China and has been widely used for its application in ornamental, oil, ecology, foraging, and food. Recent studies have revealed that the main components of Orychophragmus violaceus include flavonoids, alkaloids, phenylpropanoids, phenolic acids, terpenoids, etc., which have pharmacological activities such as antioxidation, antiradiation, antitumor, hepatic protection, antiferroptosis, anti-inflammatory, and antibacterial. In this paper, the nutritional value, chemical compositions, pharmacological activity, and application value of Orychophragmus violaceus are summarized by referring to the relevant domestic and international literature to provide a reference for further research, development, and utilization of Orychophragmus violaceus in the future.

Mild-heat photothermal antibacterial therapy avoids heat-induced damage to normal tissues but causes bacterial tolerance. The use of photothermal therapy in synergy with chemodynamic therapy is expected to address this issue. Herein, two pseudo-conjugated polymers PM123 with photothermal units and PFc with ferrocene (Fc) units are designed to co-assemble with DSPE-mPEG2000 into nanoparticle NPM123/Fc. NPM123/Fc under 1064 nm laser irradiation (NPM123/Fc+NIR-II) generates mild heat and additionally more toxic ∙OH from endogenous H2O2, displaying a strong synergistic photothermal and chemodynamic effect. NPM123/Fc+NIR-II gives >90% inhibition rates against MDR ESKAPE pathogens in vitro. Metabolomics analysis unveils that NPM123/Fc+NIR-II induces bacterial metabolic dysregulation including inhibited nucleic acid synthesis, disordered energy metabolism, enhanced oxidative stress, and elevated DNA damage. Further, NPM123/Fc+NIR-II possesses >90% bacteriostatic rates at infected wounds in mice, resulting in almost full recovery of infected wounds. Immunodetection and transcriptomics assays disclose that the therapeutic effect is mainly dependent on the inhibition of inflammatory reactions and the promotion of wound healing. What is more, thioketal bonds in NPM123/Fc are susceptible to ROS, making it degradable with highly favorable biosafety in vitro and in vivo. NPM123/Fc+NIR-II with a unique synergistic antibacterial strategy would be much less prone to select bacterial resistance and represent a promising antibiotics-alternative anti-infective measure.

The aberrant activation of immune responses mediated by Toll-like receptor 4 (TLR4) generates severe inflammatory syndromes such as acute lung injury (ALI) and sepsis, thus targeting TLR4 is attractive as a potential pharmacological therapy for these diseases. The aim of this study is to develop a novel structural TLR4 inhibitor for the treatment of ALI and sepsis. Herein, we designed and synthesized a new series of 3-bromoflavone derivatives by screening and incorporating molecular docking. Their anti-inflammatory effects were evaluated by ELISA in macrophages and compound D5 was identified as the most potential anti-inflammatory candidate. Compound D5 inhibited lipopolysaccharide (LPS)-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in RAW264.7 cells with IC50 values of 0.215 and 4.211 mu M, respectively. Immunoprecipitation, SPR, and immunoblotting demonstrated that D5 targeted TLR4-MD2 complex and competitively inhibited the binding of LPS to TLR4-MD2, resulting in inhibition of NF-kappa B and MAPK signaling pathways. In vivo administration of D5 significantly ameliorated various pathological indexes in LPS-induced ALI model and promoted the survival rate in LPS-induced septic model. Overall, our studies have identified a 3-bromoflavone derivative, D5, as a potent TLR4-MD2 antagonist and represented a very promising starting point for the development of antiinflammatory agents for the treatment of ALI and sepsis.

DMTMM was used as condensing agent for synthesis of 1,2,4-oxadiazoles from corresponding carboxylic acids and amidoximes in the mixed solvent of THF and NMP. First, carboxylic acids were activated by DMTMM, and then reacted with amidoximes to convert to O-acylated amidoximes. The unusual solvent system THF-NMP successfully promoted dehydration process of O-acylated amidoximes and 1,2,4-oxadiazoles were acquired in one-pot. This methodology provides a convenient and facile synthesis of 1,2,4-oxadiazoles with high yield.

Spleen and lymphoid organs are important targets for messenger RNA (mRNA) delivery in various applications. Current nanoparticle delivery methods rely on drainage to lymph nodes from intramuscular or subcutaneous injections. In difficult-to-transfect antigen-presenting cells (APCs), such as dendritic cells (DCs), effective mRNA transfection remains a significant challenge. In this study, a lymphatic targeting carrier using DC membranes is developed, that efficiently migrated to lymphoid organs, such as the spleen and lymph nodes. The nanoparticles contained an ionizable lipid (YK009), which ensured a high encapsulation efficacy of mRNA and assisted mRNA with endosomal escape after cellular uptake. Dendritic cell-mimicking nanoparticles (DCMNPs) showed efficient protein expression in both the spleen and lymph nodes after intramuscular injections. Moreover, in immunized mice, DCMNP vaccination elicited Spike-specific IgG antibodies, neutralizing antibodies, and Th1-biased SARS-CoV-2-specific cellular immunity. This work presents a powerful vaccine formula using DCMNPs, which represents a promising vaccine candidate for further research and development.