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Antimicrobial photodynamic inactivation (aPDI), using photosensitisers in combination with antibiotics, is a promising multi-target strategy to address antibiotic resistance, particularly in wound infections. This study aimed to elucidate the antibacterial mode of action of combinations of berberine (Ber) or curcumin (Cur) with selected antibiotics (Ber-Ab or Cur-Ab) under blue light irradiation (420 nm) against Staphylococcus aureus, including methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) strains. Multiple physiological parameters were assessed using complementary assays (fluorometry, epifluorescence microscopy, flame emission and atomic absorption spectroscopy, zeta potential, flow cytometry, and the plate agar method) to examine the effect on ROS production, membrane integrity, DNA damage, motility and virulence factors of S. aureus. Results indicated that blue light photoactivated Ber-Ab and Cur-Ab combinations led to substantial ROS generation, even at low concentrations, causing oxidative stress that severely impacted bacterial membrane integrity (approximately 90 % in MRSA and 40 % in MSSA). Membrane destabilization was further confirmed by elevated intercellular potassium release (≈ 2.00 and 2.40 µg/mL in MRSA and MSSA, respectively). Furthermore, significant DNA damage was observed in both strains (≈ 50 %). aPDI treatment with blue light also reduced S. aureus pathogenicity by impairing motility and inhibiting key virulence factors such as proteases, lipases, and gelatinases, all of which play key roles in the infectious process. Overall, Ber-Ab combinations demonstrated the highest efficacy across all parameters tested, highlighting for the first time the multi-target therapeutic potential of this phytochemical-based aPDI strategy to combat antibiotic-resistant S. aureus infections and improve wound infection treatment outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

In order to quickly and conveniently detect multiple heavy metal ions in aqueous phase simultaneously, a polyethylene glycol passivated N-doping carbon quantum (p-N-CQDs) was synthesized by a hydrothermal method with citric acid (carbon source), urea (nitrogen source) and polyethylene glycol (passivator). The as-prepared p-N-CQDs could be evenly dispersed in deionized water, and the average diameter was 1.83 nm, resulting in 18.72% of fluorescence quantum yield. As a sensor, the fluorescence of p-N-CQDs would be significantly quenched with Fe 3+ or Cu 2+ under the different maximum emission wavelength of 452 nm and 448 nm, respectively. Therefore, a method for simultaneously detecting multiple heavy metal ions was proposed by discriminative fitting of the fluorescence emission peaks after metal ion quenching. Upon the experiments, two linear calibration curves between resolving fluorescence intensities of p-N-CQDs and concentration of the metal ions were obtained within a range of 10 to 1000 µM of Cu 2+ and 40 to 800 µM of Fe 3+ . And a limit of detection (LOD) of 0.032 µM was attained after resolving the curves based on the emission wavelength of 448 nm for Cu 2+ and 452 nm for Fe 3+ by a peak splitting software. In addition, the stability, selectivity and anti-interference of the proposal senor was confirmed., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) are neurological conditions that primarily impact the elderly having distinctive traits and some similarities in terms of symptoms and progression. The multifactorial nature of AD and PD encourages exploring potentiality of multi-target therapy for addressing these conditions to conventional, the "one drug one target" strategy. This study highlights the searching of potential HDAC4 inhibitors through multiple screening approaches. In this context, structure-based pharmacophore model, ligand profiler mapping and MCDM approaches were performed for target prioritization. Similarly, ligand profiler, MCDM and Docking studies were performed to prioritize multi-targeted HDAC4 inhibitors. These comprehensive approaches unveiled 5 common targets and 5 multi-targeted prioritized compounds consensually. MD simulations, DFT and binding free energy calculations corroborated the stability and robustness of propitious compound 774 across 5 prioritized targets. In conclusion, the screened compound 774 (ChEMBL 4063938) could be a promising multi-targeted therapy for managing AD and PD further rendering experimental validation., Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00302-4., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

In this manuscript, we comment on the article by Liu et al published in the recent issue of the journal. Hyperuricemia (HUA) has become the second most common metabolic disease after type 2 diabetes mellitus and is the most important risk factor for gout. This discussion focuses on the targets and clinical application value of traditional Chinese medicine (TCM) extracts in the treatment of HUA and gout, emphasizing the role of gut microbiota. Liu et al 's study demonstrated that Poecilobdella manillensis protein extract alleviated HUA through multiple mechanisms, including inhibition of uric acid (UA) reabsorption, promotion of UA excretion, repair of intestinal barrier function, and regulation of gut microbiota and metabolome. Unlike the commonly used urate-lowering drugs such as allopurinol and febuxostat, which have clear and single targets, many TCMs have multi-target effects. However, the active components and mechanisms of TCMs are not fully understood, limiting their clinical application in the treatment of HUA and gout. Additionally, the role of gut microbiota in UA metabolic homeostasis needs to be further explored., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Multi-target strategy can serve as a valid treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but existing drugs most focus on a single target. Thus, multi-target drugs that bind multiple sites simultaneously need to be urgently studied. Apigenin has antiviral and anti-inflammatory properties. Here, we comprehensively explored the potential effect and mechanism of apigenin in SARS-CoV-2 treatment by a network algorithm, deep learning, molecular docking, molecular dynamics (MD) simulation, and normal mode analysis (NMA). KATZ-based VDA prediction method (VDA-KATZ) indicated that apigenin may provide a latent drug therapy for SARS-CoV-2. Prediction of DTA using convolution model with self-attention (CSatDTA) showed potential binding affinity of apigenin with multiple targets of virus entry, assembly, and cytokine storms including cathepsin L (CTSL), membrane (M), envelope (E), Toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), NOD-like receptor pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and cysteinyl aspartate-specific proteinase-1 (Caspase-1). Molecular docking indicated that apigenin could effectively bind these targets, and its stability was confirmed using MD simulation and NMA. Overall, apigenin is a multi-target inhibitor for the entry, assembly, and cytokine storms of SARS-CoV-2., (© 2024 Federation of American Societies for Experimental Biology.)

The discovery of a multi-target scaffold in medicinal chemistry is an important goal for the development of new drugs with different biological effects. Azobenzene is one of the frameworks in medicinal chemistry used for its simple synthetic methods and for the possibility to obtain a great variety of derivatives by simple chemical modifications or substitutions. Phenyldiazenyl-containing compounds show a wide spectrum of pharmacological activities, such as antimicrobial, anti-inflammatory, anti-neurodegenerative, anti-cancer, and anti-enzymatic. The aim of this review is to highlight the importance of azobenzene as a scaffold in medicinal chemistry, with particular attention to the chemical modifications and structure-activity relationships (SARs). This review emphasizes the main therapeutic applications of phenyldiazenyl derivatives, with a particular focus on structural modification and its influence on activity, with the aim of inspiring medicinal chemists to obtain new, increasingly powerful azobenzenes useful in therapy.

In this current work, we dedicated efforts to designing and synthesizing new 1,2,3-triazole-analogues (5a-d), (6a-d), and (7a-c) to act as dual VEGFR-2 and telomerase inhibitors with promising apoptotic potential. The synthesized analogues were examined against eleven diverse types of cancer cells and two normal cells to assess their ability to inhibit cell growth (GI%). Obviously, compound 7b showed the best average GI% (75.69 %) surpassing the average GI% of Dox (65.79 %). Compound 5d showed the lowest IC 50 values (25.86 and 51.91 µM) against HNO-97 and FaDu cancer cells, respectively. Besides, compound 5a exhibited the lowest IC 50 value (15.46 µM) against HCT 116 , whereas compound 6b revealed the lowest IC 50 value (31.14 µM) against HuH7. Besides, candidates 5a, 5b, 5d, and 7a showed prominent inhibitory results towards VEGFR-2 protein with decreasing its expression by 0.33, 0.42, 0.38 and 0.26-fold change, respectively. However, compounds 5a, 5b, 5d, and 7a showed promising inhibitory results towards telomerase protein and decreased its expression by 0.60, 0.50, 0.52, and 0.44-fold change, respectively. Additionally, it was clear that compound 5a was able to upregulate the expression of Caspases 3, 8, and 9 proteins by 2.19, 1.83, and 1.62-fold change, respectively. Besides, 5a was able to downregulate the expression of CDK-2, CDK-4, and CDK-6 proteins by 0.50, 0.43, and 0.13-fold change, respectively. Obviously, compound 5a halted the cell cycle at the G1, S, and G2-M phases in HCT 116 cells. Subsequently, the synthesized 1,2,3-triazole analogues can be treated as lead VEGFR-2 and telomerase inhibitors with potential apoptotic activity for future optimization and cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Natural drugs possess exceptional pharmacological properties, yet their development is often hindered by a lack of clarity regarding the mechanisms of their pharmacological actions. Building on our previous research, we employed a co-infection model with Mycoplasma gallisepticum (MG) and Escherichia coli (E. coli) to investigate the pharmacological action of Radix Isatidis Mixtures (RIM). To further demonstrate the various mechanisms underlying the pharmacological effects of RIM, we conducted a validation study focusing on gene expression, protein interactions, metabolic pathways, and molecular docking. Through a multi-omics joint analysis network, we identified key targets and metabolites associated with co-infection and conducted targeted verification experiments with RIM aqueous extracts. The experimental results indicated that, compared to the co-infection group, the RIM treatment group significantly modulated the expression of select genes and proteins, particularly MMP2 and TLR4, with a high level of statistical significance (p < 0.01). At the metabolic level, the treatment group exhibited significantly reduced expression levels of Dopamine and γ-Aminobutyric acid. Notably, the molecular docking results highlighted compounds with the most favorable binding affinities: Salvianolic acid A (-10.1 kcal/mol), Licorice (-9.3 kcal/mol), and Isoglycyrrhiza (-8.7 kcal/mol). In conclusion, our multi-level experiments demonstrated that RIM possesses the characteristics of multi-pathway and multi-target treatment for co-infection., (Copyright © 2024. Published by Elsevier Inc.)

In this study, a series of novel arylpropylamine derivatives were designed, synthesized and evaluated as potential multi-target antidepressants. Among them, compound (R)-13j displayed unique pharmacological features, exhibiting excellent inhibitory potency against serotonin and noradrenaline transporters (SERT/NET) and high affinity for 5-HT 2A / 2C receptor, and showing low affinity for histamine H 1 , adrenergic α 1 receptors and hERG channels (to reduce QT interval prolongation). Molecular docking studies provided a rational binding model of (R)-13j in complex with SERT and 5-HT 2A/2C receptor. In animal models, compound (R)-13j dose-dependently reduced the immobility time in the tail suspension test (TST) and the forced swimming test (FST) in mice, with higher efficacy when compared to duloxetine, and showed no stimulatory effect on the locomotor activity. Moreover, compound (R)-13j significantly shortened the immobility time in the ACTH-induced rat model of treatment-resistant depression (TRD). Furthermore, compound (R)-13j also exhibited a higher threshold for acute toxicity than duloxetine. In addition, compound (R)-13j possessed a favorable pharmacokinetic profile in mice. Taken together, compound (R)-13j may constitute a novel class of drugs for the treatment of depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Honey, a widely consumed food, is susceptible to contamination by various toxic substances during production. Tropane alkaloids, with their potent neurotoxicity, are frequently found in honey. Hence, there is an acute need for rapid and effective detection methods to monitor these alkaloids. Lateral flow immunoassay (LFIA), known for its simple operation, low cost, and reliable results, holds great promise. In this study, we developed an efficient and user-friendly analytical method for the simultaneous detection of six tropane alkaloids (atropine, L-hyoscyamine, scopolamine, anisodamine, homatropine, and apoatropine) in honey based on an AuNPs lateral flow immunoassay (AuNPs-LFIA) with broad-spectrum antibodies. Under optimal conditions, the calculated detection limits were 0.22, 0.29, 0.51, 6.34, 0.30, and 0.94 ng/mL, respectively. By diluting the honey sample five times, the contaminants can be readily detected using LFIA. Semi-quantitative and quantitative analyses can be completed within 17 min. This innovative method fills the void in LFIA for detecting tropane alkaloids and serves as a valuable reference for LFIA detection of honey samples, providing a crucial strategy for the accurate detection of these important compounds.

For the last two decades, the aromatic aldehyde 5-hydroxymethyl-furfural (5-HMF) has been the subject of several investigations for its pharmacologic potential. In 2004, the Safo group reported that 5-HMF has potent antisickling activity by targeting and ameliorating the primary pathophysiology of hypoxia-induced sickling of erythrocytes (red blood cells [RBC]). Following the encouraging outcome of the preclinical and phase I/II clinical studies of 5-HMF for the treatment of sickle cell disease (SCD), there have been multiple studies suggesting 5-HMF has several other biological or pharmacologic activities, including anti-allergic, antioxidant, anti-hypoxic, anti-ischemic, cognitive improvement, anti-tyrosinase, anti-proliferation, cytoprotective, and anti-inflammatory activities. The wide range of its effects makes 5-HMF a potential candidate for treating a variety of diseases including cognitive disorders, gout, allergic disorders, anemia, hypoxia, cancers, ischemia, hemorrhagic shock, liver fibrosis, and oxidative injury. Several of these therapeutic claims are currently under investigation and, while promising, vary in terms of the strength of their evidence. This review presents the research regarding the therapeutic potential of 5-HMF in addition to its sources, physicochemical properties, safety, absorption, distribution, metabolism, and excretion (ADME) profiles., (© 2024 The Author(s). Medicinal Research Reviews published by Wiley Periodicals LLC.)

When multi-dynamic target UAVs escape, the uncertainty of the formation method and the external environment causes difficulties in rounding them up, so suitable solutions are needed to improve the roundup success rate. However, traditional methods can generally only enable the encirclement of a single target, and when the target is scattered and escaping, this will lead to encirclement failure due to the inability to sufficiently allocate UAVs for encirclement. Therefore, in this paper, a real-time roundup and dynamic allocation algorithm for multiple dynamic targets is proposed. A real-time dynamic obstacle avoidance model is established for the roundup problem, drawing on the artificial potential field function. For the escape problem of the rounding process, an optimal rounding allocation strategy is established by drawing on the linear matching method. The algorithm in this paper simulates the UAV in different obstacle environments to round up dynamic targets with different escape methods. The results show that the algorithm is able to achieve the rounding up of multiple dynamic targets in a UAV and obstacle scenario with random initial positions, and the task UAV, which is able to avoid obstacles, can be used in other algorithms for real-time rounding up and dynamic allocation. The results show that the algorithm is able to achieve the rounding up of multi-dynamic targets in scenarios with a random number of UAVs and obstacles with random locations. It results in a 50% increase in the rounding efficiency and a 10-fold improvement in the formation success rate. And the mission UAV is able to avoid obstacles, which can be used in other algorithms for real-time roundup and dynamic allocation.

Ethnopharmacological Relevance: Parasitic infections impose a significant burden on public health worldwide. European pharmacopoeia records and ethnopharmacological studies indicate that Hagenia abyssinica (Bruce) J.F. Gmel. has traditionally been used to treat a variety of parasitic infections, while the potential antiparasitic compounds remain ambiguous., Aim of the Study: Acetylcholinesterase (AChE), lactate dehydrogenases (LDH), and glutathione reductase (GR) are the key target enzymes in the survival of parasites. The aim of our work was to screen antiparasitic compounds targeting AChE, LDH, and GR from H. abyssinica., Materials and Methods: Ultrafiltration-liquid chromatography-mass spectrometry (UF-LC-MS) combined with molecular docking was used in this study. Therein, the alamarBlue® and Ellman's methods were employed to reveal the antitrypanosomal effect and AChE inhibitory activity. Meanwhile, the UF-LC-MS was carried out to screen the potential active compounds from H. abyssinica. Subsequently, molecular docking was performed to evaluate the binding mechanisms of these active compounds with AChE, LDH, and GR. Finally, the AChE inhibitory activity of potential inhibitors was detected in vitro., Results: H. abyssinica exhibited significant antitrypanosomal and AChE inhibitory activity. Corilagin, brevifolin carboxylic acid, brevifolin, quercetin, and methyl ellagic acid were recognized as potential AChE inhibitors by UF-LC-MS, while methyl brevifolin carboxylate was identified as AChE, LDH, and GR multi-target inhibitor, with binding degree ranged from 20.96% to 49.81%. Molecular docking showed that these potential inhibitors had a strong affinity with AChE, LDH, and GR, with binding energies ranging from -6.98 to -9.67 kcal/mol. These findings were further supported by the observation that corilagin, quercetin, brevifolin carboxylic acid, and methyl brevifolin carboxylate displayed significant AChE inhibitory activity compared with the positive control (gossypol, 0.42 ± 0.04 mM), with IC 50 values of 0.15 ± 0.05, 0.56 ± 0.03, 0.99 ± 0.01, and 1.02 ± 0.03 mM, respectively., Conclusions: This study confirms the antiparasitic potential of H. abyssinica, supporting the traditional use of H. abyssinica in local ethnopharmacology to treat parasites. At the same time, corilagin, brevifolin carboxylic acid, brevifolin, quercetin, methyl ellagic acid, and methyl brevifolin carboxylate exert their anti-parasitic effects by inhibiting AChE, LDH, and GR, and they are expected to be natural lead compounds for the treatment of parasitic diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pharmacological investigations have substantiated the potential of bifunctional opioid/cannabinoid agonists in delivering potent analgesia while minimizing adverse reactions. Peptide modulators of cannabinoid receptors, known as pepcans, have been investigated before. In this study, we designed a series of chimeric peptides based on pepcans and morphiceptin (YPFP-NH 2 ). Here, we combined injections of pepcans and morphiceptin to investigate the combination treatment of opioids and cannabis and compared the analgesic effect with chimeric compounds. Subsequently, we employed computational docking to screen the compounds against opioid and cannabinoid receptors, along with an acute pain model, to identify the most promising peptide. Among these peptides, MP-13, a morphiceptin and pepcan-9 (PVNFKLLSH) construct, exhibited superior supraspinal analgesic efficacy in the tail-flick test, with an ED 50 value at 1.43 nmol/mouse, outperforming its parent peptides and other chimeric analogs. Additionally, MP-13 displayed potent analgesic activity mediated by mu-opioid receptor (MOR), delta-opioid receptor (DOR), and cannabinoid type 1 (CB1) receptor pathways. Furthermore, MP-13 did not induce psychological dependence and gastrointestinal motility inhibition at the effective analgesic doses, and it maintained non-tolerance-forming antinociception throughout a 7-day treatment regimen, with an unaltered count of microglial cells in the periaqueductal gray region, supporting this observation. Moreover, intracerebroventricular administration of MP-13 demonstrated dose-dependent antinociception in murine models of neuropathic, inflammatory, and visceral pain. Our findings provide promising insights for the development of opioid/cannabinoid peptide agonists, addressing a crucial gap in the field and holding significant potential for future research and development. PERSPECTIVE: This article offers insights into the combination treatment of pepcans with morphiceptin. Among the chimeric peptides, MP-13 exhibited potent analgesic effects in a series of preclinical pain models with a favorable side-effect profile., Competing Interests: Declaration of competing interest All authors confirm that this article content has no conflict of interest. We have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Histone deacetylase inhibitors (HDACis) show beneficial effects on different hematological malignancy subtypes. However, their impacts on treating solid tumors are still limited due to diverse resistance mechanisms. Recent studies have found that the feedback activation of BRD4-LIFR-JAK1-STAT3 pathway after HDACi incubation is a vital mechanism inducing resistance of specific solid tumor cells to HDACis. This review summarizes the recent development of multi-target HDACis that can concurrently block BRD4-LIFR-JAK1-STAT3 pathway. Moreover, our findings hope to shed novel lights on developing novel multi-target HDACis with reduced BRD4-LIFR-JAK1-STAT3-mediated drug resistance in some tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

In modern radar detection systems, the particle filter technique has become one of the core algorithms for real-time target detection and tracking due to its good nonlinear and non-Gaussian system state estimation capability. However, when dealing with complex dynamic scenes, the traditional particle filter algorithm exposes obvious deficiencies. The main expression is that the sample degradation is serious, which leads to a decrease in estimation accuracy. In multi-target states, the algorithm is difficult to effectively distinguish and stably track each target, which increases the difficulty of state estimation. These problems limit the application potential of particle filter technology in multi-target complex environments, and there is an urgent need to develop a more advanced algorithmic framework to enhance its robustness and accuracy in complex scenes. Therefore, this paper proposes an improved particle filter algorithm for multi-target detection and tracking. Firstly, the particles are divided into tracking particles and searching particles. The tracking particles are used to maintain and update the trajectory information of the target, and the searching particles are used to identify and screen out multiple potential targets in the environment, to sufficiently improve the diversity of the particles. Secondly, the density-based spatial clustering of applications with noise is integrated into the resampling phase to improve the efficiency and accuracy of particle replication, so that the algorithm can effectively track multiple targets. Experimental result shows that the proposed algorithm can effectively improve the detection probability, and it has a lower root mean square error (RMSE) and a stronger adaptability to multi-target situation.

4,9-diaminoacridines with reported antiplasmodial activity were coupled to different trans-cinnamic acids, delivering a new series of conjugates inspired by the covalent bitherapy concept. The new compounds were more potent than primaquine against hepatic stages of Plasmodium berghei, although this was accompanied by cytotoxic effects on Huh-7 hepatocytes. Relevantly, the conjugates displayed nanomolar activities against blood stage P. falciparum parasites, with no evidence of hemolytic effects below 100 µM. Moreover, the new compounds were at least 25-fold more potent than primaquine against P. falciparum gametocytes. Thus, the new antiplasmodial hits disclosed herein emerge as valuable templates for the development of multi-stage antiplasmodial drug candidates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Based on the crucial role of histone deacetylase (HDAC) and receptor tyrosine kinase in angiogenesis, in situ assembly, skeletal transition, molecular hybridization, and pharmacophore fusion were employed to yield seventy-six multi-target angiogenesis inhibitors. Biological evaluation indicated that most of the compounds exhibited potent proliferation inhibitory activity on MCF-7 cells, with the TH series having the highest inhibitory activity on MCF-7 cells. In addition, the IC 50 values of TA11 and TH3 against HT-29 cellswere 0.078 μmol/L and 0.068 μmol/L, respectively. The cytotoxicity evaluation indicated that TC9, TA11, TM4, and TH3 displayed good safety against HEK293T cells. TH2 and TH3 could induce apoptosis of MCF-7 cells. Molecular modeling and ADMET prediction results indicated that most of target compounds showed promising medicinal properties, which was consistent with the experimental results. Our findings provided new lead compounds for the structural optimization of multi-target angiogenesis inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

After the decline of the COVID-19 pandemic, health systems were challenged by the simultaneous prevalence of different respiratory viruses causing a wide overlap in symptoms. This increased the demand for multi-virus diagnostic tests which require suitable pre-analytical workflow solutions in order to receive valid diagnostic results. In this context, the effects of specimen storage duration and temperature on the RNA/DNA copy number stability of influenza A/B, RSV A/B, SARS-CoV-2 and adenovirus were examined for four commercially available transport swab systems and saliva collection devices. The respiratory viruses were more stable in the saliva collection devices than in the transport swab systems when stored at RT or 37 °C for up to 96 h. Moreover, no differences between viral nucleic acid stability of enveloped and non-enveloped viruses were observed. The infectivity of all enveloped viruses could be inactivated by the saliva collection device from PreAnalytiX. The Norgen saliva device completely inactivated influenza A/B, while RSV A/B were partially inactivated. The non-enveloped adenovirus was inactivated by a reduction factor of 10E+ 4 in both saliva collection devices. All respiratory viruses remained infectious in the transport swab systems. Two possible transport medium additives were tested which inactivated or strongly reduced viral replication of tested enveloped viruses but had no effect on the non-enveloped adenovirus. Finally the implementation of multi-target detection procedures involving a direct amplification approach was successfully tested by spike-in of all enveloped viruses simultaneously into transport swab systems. This fast and reproducible setup presents a valuable solution for future implementations in multi-virus testing strategies., Competing Interests: Declaration of Competing Interest Franziska Kaiser, Uwe Oelmüller, Thorsten Voss, Katrin Rodenkirchen are employees of QIAGEN GmbH Hilden, Germany. Uwe Oelmüller and Thorsten Voss participate in QIAGEN’s regular long term incentive program (LTIs). Uwe Oelmüller is Co-chair of PreAnalytiX management board. Kurt Zatloukal is co-founder and CEO of Zatloukal Innovations GmbH., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Alzheimer's disease (AD) is the most common neurodegenerative disease, and its multifactorial nature increases the difficulty of medical research. To explore an effective treatment for AD, a series of novel tacrine-selegiline hybrids with ChEs and MAOs inhibitory activities were designed and synthesized as multifunctional drugs., Methods: All designed compounds were evaluated in vitro for their inhibition of cholinesterases (AChE/BuChE) and monoamine oxidases (MAO-A/B) along with their blood-brain barrier permeability. Then, further biological activities of the optimizing compound 7d were determined, including molecular model analysis, in vitro cytotoxicity, acute toxicity studies in vivo, and pharmacokinetic and pharmacodynamic property studies in vivo., Results: Most synthesized compounds demonstrated potent inhibitory activity against ChEs/MAOs. Particularly, compound 7d exhibited good and well-balanced activity against ChEs ( h AChE: IC 50 = 1.57 μM, h BuChE: IC 50 = 0.43 μM) and MAOs ( h MAO-A: IC 50 = 2.30 μM, h MAO-B: IC 50 = 4.75 μM). Molecular modeling analysis demonstrated that 7d could interact simultaneously with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE in a mixed-type manner and also exhibits binding affinity towards BuChE and MAO-B. Additionally, 7d displayed excellent permeability of the blood-brain barrier, and under the experimental conditions, it elicited low or no toxicity toward PC12 and BV-2 cells. Furthermore, 7d was not acutely toxic in mice at doses up to 2500 mg/kg and could improve the cognitive function of mice with scopolamine-induced memory impairment. Lastly, 7d possessed well pharmacokinetic characteristics., Conclusion: In light of these results, it is clear that 7d could potentially serve as a promising multi-functional drug for the treatment of AD., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Huang et al.)

X-ray communication is a kind of space communication technology which uses X-ray as information carrier. In order to improve the information transmission capacity, communication rate and anti-interference ability of X-ray communication, we proposes to design a novel multi-target X-ray source. The source is composed of a fast switching module of light channels based on FPGA technology and four photoelectric X-ray tubes with different target materials: Cr, Fe, Ni, and Cu. Using Geant4 software, we determined the optimal target thickness for each material, which enabled us to fully leverage the characteristic X-rays for multi-channel signal modulation transmission. Moreover, using CST software for particle trajectory simulation and optimization of the electron beam revealed that at a tube voltage of 20 kV, the focus area measures approximately 1.2 mm×1.2 mm. The simulations show that four kinds of spectra with high distinctiveness can be generated from the Cr, Fe, Ni, and Cu targets. Within a single modulation period, these spectra can be combined in various ways to create 16 different X-ray spectra signals, thereby increasing the number of communication elements and enhancing the information transmission rate.

Progressive cognitive decline in Alzheimer's disease (AD) is a growing challenge. Present therapies are based on acetylcholinesterase inhibition providing only temporary relief. Promising alternatives include butyrylcholinesterase (BuChE) inhibitors, multi-target ligands (MTDLs) that address the multi-factorial nature of AD, and compounds that target oxidative stress and inflammation. Cinnamate derivatives, known for their neuroprotective properties, show potential when combined with established AD agents, demonstrating improved efficacy. They are being positioned as potential AD therapeutic leads due to their ability to inhibit Aβ accumulation and provide neuroprotection. This article highlights the remarkable potential of cinnamic acid as a basic structure that is easily adaptable and combinable to different active groups in the struggle against Alzheimer's disease. Compounds with a methoxy substitution at the para-position of cinnamic acid display increased efficacy, whereas electron-withdrawing groups are generally more effective. The effect of the molecular volume is worthy of further investigation.

Epilepsy is a neurological disease with no defined cause, characterized by recurrent epileptic seizures. These occur due to the dysregulation of excitatory and inhibitory neurotransmitters in the central nervous system (CNS). Psychopharmaceuticals have undesirable side effects; many patients require more than one pharmacotherapy to control crises. With this in mind, this work emphasizes the discovery of new substances from natural products that can combat epileptic seizures. Using in silico techniques, this review aims to evaluate the antiepileptic and multi-target activity of phenylpropanoid derivatives. Initially, ligand-based virtual screening models (LBVS) were performed with 468 phenylpropanoid compounds to predict biological activities. The LBVS were developed for the targets alpha- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), voltage-gated calcium channel Ttype (CaV), gamma-aminobutyric acid A (GABAA), gamma-aminobutyric acid transporter type 1 (GAT-1), voltage-gated potassium channel of the Q family (KCNQ), voltage-gated sodium channel (NaV), and N-methyl D-aspartate (NMDA). The compounds that had good results in the LBVS were analyzed for the absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and later, the best molecules were evaluated in the molecular docking consensus. The TR430 compound showed the best results in pharmacokinetic parameters; its oral absorption was 99.03%, it did not violate any Lipinski rule, it showed good bioavailability, and no cytotoxicity was observed either from the molecule or from the metabolites in the evaluated parameters. TR430 was able to bind with GABAA (activation) and AMPA (inhibition) targets and demonstrated good binding energy and significant interactions with both targets. The studied compound showed to be a promising molecule with a possible multi-target activity in both fundamental pharmacological targets for the treatment of epilepsy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Molecular hybridization has emerged as a promising approach in the treatment of diseases exhibiting multifactorial etiology. With regard to this, dual cyclooxygenase-2/lipoxygenase (COX-2/LOX) inhibitors could be considered a safe alternative to traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs) for the treatment of inflammatory conditions. Taking this into account, six novel pyrrole derivatives and pyrrole-cinnamate hybrids were developed as potential COX-2 and soybean LOX (sLOX) inhibitors with antioxidant activity. In silico calculations were performed to predict their ADMET (absorption, distribution, metabolism, excretion, toxicity) properties and drug-likeness, while lipophilicity was experimentally determined as R M values. All synthesized compounds ( 1 - 4 , 5 - 8 ) could be described as drug-like. The results from the docking studies on COX-2 were in accordance with the in vitro studies. According to molecular docking studies on soybean LOX, the compounds displayed allosteric interactions with the enzyme. Pyrrole 2 appeared to be the most potent s-LOX inhibitor (IC 50 = 7.5 μM). Hybrids 5 and 6 presented a promising combination of in vitro LOX (IC 50 for 5 = 30 μM, IC 50 for 6 = 27.5 μM) and COX-2 (IC 50 for 5 = 0.55 μM, IC 50 for 6 = 7.0 μM) inhibitory activities, and therefore could be used as the lead compounds for the synthesis of more effective multi-target agents.

Insomnia is a common and refractory disease. Since more than 2000 years ago, people have been using Ziziphi Spinosae Semen (ZSS). However, there are lack of molecular mechanisms of sleep promotion effects of ZSS. The purpose of this study is to clarify the active ingredients in ZSS that are used to treat insomnia. Using a method called cellular label-free integrative pharmacology (CLIP), we established five insomnia-related target models, including serotonin (5HT 2A and 5HT 1A ), melatonin (MT 1 ), dopamine (D 2 ) and epinephrine (β 2 ) receptors. The one-dimensional (1D) fractions of ZSS extract were prepared on a RZC18 column and assayed on five models. Subsequently, the active fraction was further analyzed, fractionated and quantified using a two-dimensional (2D) liquid phase method coupled with a charged aerosol detector (CAD), This CAD-coupled 2D-LC method requires micro-fractions from the 1D separation and thus it greatly saves sample amounts and corresponding preparation time, and quickly conduct activity screening. The composition of the active 2D fractions was then determined using three-dimensional (3D) HPLC-MS, and molecular docking was separately carried out for the described compounds on the targets for activity prediction. Seven compounds were predicted to be active on 5HT 2A , and two compounds on D 2 . We experimentally verified the prediction and found that vitexin exhibited D 2 agonistic activity, and nuciferine exhibited 5HT 2A antagonistic activity. This study revealed the effective components and their targets of ZSS in the treatment of insomnia, also highlighted the potential of the CLIP technique and bioactivity guided multi-dimensional HPLC-MS in molecular mechanism elucidation for traditional Chinese medicines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Nut quality detection is of paramount importance in primary nut processing. When striving to maintain the imperatives of rapid, efficient, and accurate detection, the precision of identifying small-sized nuts can be substantially compromised., Methods: We introduced an optimized iteration of the YOLOv5s model designed to swiftly and precisely identify both good and bad walnut nuts across multiple targets. The M3-Net network, which is a replacement for the original C3 network in MobileNetV3's YOLOv5s, reduces the weight of the model. We explored the impact of incorporating the attention mechanism at various positions to enhance model performance. Furthermore, we introduced an attentional convolutional adaptive fusion module (Acmix) within the spatial pyramid pooling layer to improve feature extraction. In addition, we replaced the SiLU activation function in the original Conv module with MetaAconC from the CBM module to enhance feature detection in walnut images across different scales., Results: In comparative trials, the YOLOv5s&#95;AMM model surpassed the standard detection networks, exhibiting an average detection accuracy (mAP) of 80.78%, an increase of 1.81%, while reducing the model size to 20.9 MB (a compression of 22.88%) and achieving a detection speed of 40.42 frames per second. In multi-target walnut detection across various scales, the enhanced model consistently outperformed its predecessor in terms of accuracy, model size, and detection speed. It notably improves the ability to detect multi-target walnut situations, both large and small, while maintaining the accuracy and efficiency., Discussion: The results underscored the superiority of the YOLOv5s&#95;AMM model, which achieved the highest average detection accuracy (mAP) of 80.78%, while boasting the smallest model size at 20.9 MB and the highest frame rate of 40.42 FPS. Our optimized network excels in the rapid, efficient, and accurate detection of mixed multi-target dry walnut quality, accommodating lightweight edge devices. This research provides valuable insights for the detection of multi-target good and bad walnuts during the walnut processing stage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhan, Li, Lin, Lv, Zhang, Li, Zhang and Zeng.)

Background: Mycotoxin contaminated food poses a threat to human health. On-site detection of mycotoxin contamination is of significance to reduce the agricultural and food industries loss. Lateral flow immunochromatography (LFIC) as on-site detection method for mycotoxins has the advantages of low cost, easy to operate and short time-consuming. Of the various types of LFIC, photothermal LFIC possesses better sensitivity and stronger quantitative capability, but is unable to conduct synchronous multi-target analysis because that the laser can only activate one test area at a time. It was clear that a synchronous multi-target photothermal LFIC method was needed., Results: In this study, a photothermal LFIC method for the simultaneous detection of three mycotoxins, deoxynivalenol (DON), aflatoxin B 1 (AFB 1 ) and zearalenone (ZEN), was developed. We broadened the laser source with a beam expander and realized the irradiation and activation of three test zones simultaneously. In addition, the competitive photothermal LFIC was constructed by using Cu 2-x Se-Au nanocomposites with excellent photothermal properties (η = 87.47%) as photothermal signal probes and thermal imager as photothermal signal collector. Under optimized experimental conditions, the limits of detection (LOD) were 73 ng L -1 , 45 ng L -1 and 43 ng L -1 for DON, AFB 1 and ZEN, respectively. The method had good linearity in three orders of magnitude and good specificity. The recoveries of the three mycotoxins in oat, cornmeal and millet samples ranged from 78.6% to 112.4%., Significance: Compared with previous studies, this method improved the sensitivity, broadened the linear range of detection without large equipment and realized synchronous multi-target analysis for DON, AFB 1 and ZEN. We addressed a key limitation of photothermal LFIC by a simple way, facilitating the application of this technique in multi-target on-site detection in wider fields., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines obtained exhibited in vitro activity in the low- or sub-micromolar range against (i) hepatic stages of Plasmodium berghei, (ii) erythrocytic forms of Plasmodium falciparum, and (iii) early and mature gametocytes of Plasmodium falciparum. The most active compound, having a meta-fluorocinnamoyl group linked to the acridine core, was 20- and 120-fold more potent, respectively, against the hepatic and gametocyte stages of Plasmodium infection than the reference drug, primaquine. Moreover, no cytotoxicity towards mammalian and red blood cells at the concentrations tested was observed for any of the compounds under investigation. These novel conjugates represent promising leads for the development of new multi-target antiplasmodials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Visceral leishmaniasis (VL) is caused by Leishmania donovani. The purine and pyrimidine pathways are essential for L. donovani. Simultaneously inhibiting multiple targets could be an effective strategy to eliminate the pathogen and treat VL., Objective: We aimed to target the essential enzymes of L. donovani and inhibit them using a multi-target approach., Materials and Methods: A systematic analytical method was followed, in which first reported inhibitors of two essential enzymes (adenine phosphoribosyl-transferase [APRT] and dihydroorotate dehydrogenase [DHODH]) were collected and then ADMET and PASS analyses were conducted using the Lipinski rule and Veber's rule. Additionally, molecular docking between screened ligands and proteins were performed. The stability of complexes was analyzed using molecular dynamics (MD) simulations and MMPBSA analysis., Results: Initially, 6,220 unique molecules were collected from the PubChem database, and then the Lipinski rule and Veber's rule were used for screening. In total, 203 compounds passed the ADMET test; their antileishmanial properties were tested by PASS analysis. As a result, 15 ligands were identified. Molecular docking simulations between APRT or DHODH and these 15 ligands were performed. Four molecules were found to be plant-derived compounds. Lig&#95;2 and Lig&#95;3 had good docking scores with both proteins. MD simulations were performed to determine the dynamic behavior and binding patterns of complexes. Both MD simulations and MMPBSA analysis showed Lig&#95;3 is a promising antileishmanial inhibitor of both targets., Conclusion: Promising plant-derived compounds that might be used to combat VL were obtained through a multi-target approach., (© 2023 John Wiley & Sons Ltd.)

The COVID-19 pandemic evolves constantly, requiring adaptable solutions to combat emerging SARS-CoV-2 variants. To address this, we created a pentameric scaffold based on a mammalian protein, which can be customized with up to 10 protein binding modules. This molecular scaffold spans roughly 20 nm and can simultaneously neutralize SARS-CoV-2 Spike proteins from one or multiple viral particles. Using only two different modules targeting the Spike's RBD domain, this construct outcompetes human antibodies from vaccinated individuals' serum and blocks in vitro cell attachment and pseudotyped virus entry. Additionally, the multibodies inhibit viral replication at low picomolar concentrations, regardless of the variant. This customizable multibody can be easily produced in procaryote systems, providing a new avenue for therapeutic development and detection devices, and contributing to preparedness against rapidly evolving pathogens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Abreu, Ortega, Olivero-Deibe, Carrión, Gaete-Argel, Valiente-Echeverría, Soto-Rifo, Milan Bonotto, Marcello and Pantano.)

Nondestructive detection of the nutritional parameters of pork is of great importance. This study aimed to investigate the feasibility of applying hyperspectral image technology to detect the nutrient content and distribution of pork nondestructively. Hyperspectral cubes of 100 pork samples were collected using a line-scan hyperspectral system, the effects of different preprocessing methods on the modeling effects were compared and analyzed, the feature wavelengths of fat and protein were extracted, and the full-wavelength model was optimized using the regressor chains (RC) algorithm. Finally, pork's fat, protein, and energy value distributions were visualized using the best prediction model. The results showed that standard normal variate was more effective than other preprocessing methods, the feature wavelengths extracted by the competitive adaptive reweighted sampling algorithm had better prediction performance, and the protein model prediction performance was optimized after using the RC algorithm. The best prediction models were developed, with the correlation coefficient of prediction (R P ) = 0.929, the root mean square error in prediction (RMSEP) = 0.699% and residual prediction deviation (RPD) = 2.669 for fat, and R P  = 0.934, RMSEP = 0.603% and RPD = 2.586 for protein. The pseudo-color maps were helpful for the analysis of nutrient distribution in pork. Hyperspectral image technology can be a fast, nondestructive, and accurate tool for quantifying the composition and assessing the distribution of nutrients in pork., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The spreading of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across the world has impacted people's health and lives worldwide in recent years. Rapid and accurate diagnosis is crucial for curbing the pandemic of coronavirus disease 2019 (COVID-19). Reverse transcription loop-mediated isothermal amplification (RT-LAMP) has great potential for SARS-CoV-2 detection but fails to completely replace conventional PCR due to the high false-positive rate (FPR). We proposed a triple-target RT-LAMP method for dual-signal, sensitive, and simultaneous detection of conserved genes of SARS-CoV-2. Multiple LAMP primer sets were designed for N, E, and M genes and their amplification efficacy were screened. Then, using artificial plasmids and RNA, the optimal primer set for each gene was examined on specificity, sensitivity, and detection range. The RT-LAMP initiated by these primer sets exhibited better specificity and sensitivity than that of RT-qPCR, and the triple-target RT-LAMP could determine different variants of SARS-CoV-2. By testing 78 artificial RNA samples, the total FPR of triple-target RT-LAMP was eliminated compared with that of mono-target RT-LAMP. The triple-target RT-LAMP method precisely identified throat swab specimens through colorimetry and fluorescent signals within 60 min, and the limit of detection (LOD) was as low as 187 copies/reaction. In the future, the triple-target RT-LAMP can be applied to in-field and on-site diagnosis of symptomatic and asymptomatic virus carriers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Vision-based target detection and segmentation has been an important research content for environment perception in autonomous driving, but the mainstream target detection and segmentation algorithms have the problems of low detection accuracy and poor mask segmentation quality for multi-target detection and segmentation in complex traffic scenes. To address this problem, this paper improved the Mask R-CNN by replacing the backbone network ResNet with the ResNeXt network with group convolution to further improve the feature extraction capability of the model. Furthermore, a bottom-up path enhancement strategy was added to the Feature Pyramid Network (FPN) to achieve feature fusion, while an efficient channel attention module (ECA) was added to the backbone feature extraction network to optimize the high-level low resolution semantic information graph. Finally, the bounding box regression loss function smooth L1 loss was replaced by CIoU loss to speed up the model convergence and minimize the error. The experimental results showed that the improved Mask R-CNN algorithm achieved 62.62% mAP for target detection and 57.58% mAP for segmentation accuracy on the publicly available CityScapes autonomous driving dataset, which were 4.73% and 3.96%% better than the original Mask R-CNN algorithm, respectively. The migration experiments showed that it has good detection and segmentation effects in each traffic scenario of the publicly available BDD autonomous driving dataset.

Cannabidiol (CBD) is a major phytocannabinoid present in Cannabis sativa (Linneo, 1753). This naturally occurring secondary metabolite does not induce intoxication or exhibit the characteristic profile of drugs of abuse from cannabis like Δ 9 -tetrahydrocannabinol (∆ 9 -THC) does. In contrast to ∆ 9 -THC, our knowledge of the neuro-molecular mechanisms of CBD is limited, and its pharmacology, which appears to be complex, has not yet been fully elucidated. The study of the pharmacological effects of CBD has grown exponentially in recent years, making it necessary to generate frequently updated reports on this important metabolite. In this article, a rationalized integration of the mechanisms of action of CBD on molecular targets and pharmacological implications in animal models and human diseases, such as epilepsy, pain, neuropsychiatric disorders, Alzheimer's disease, and inflammatory diseases, are presented. We identify around 56 different molecular targets for CBD, including enzymes and ion channels/metabotropic receptors involved in neurologic conditions. Herein, we compiled the knowledge found in the scientific literature on the multiple mechanisms of actions of CBD. The in vitro and in vivo findings are essential for fully understanding the polypharmacological nature of this natural product.

Growing evidence has associated major depressive disorder (MDD) as a risk factor or prodromal syndrome for the occurrence of Alzheimer's disease (AD). Although this dilemma remains open, it is widely shown that a lifetime history of MDD is correlated with faster progression of AD pathology. Therefore, antidepressant drugs with neuroprotective effects could be an interesting therapeutic conception to target this issue simultaneously. In this sense, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) was initially conceived as a multi-target ligand with affinity to β-secretase (BACE), glycogen synthase kinase 3β (GSK3β), and acetylcholinesterase but has also shown secondary effects on pathways involved in neuroinflammation and neurogenesis in preclinical models of AD. Herein, we investigated the effect of QTC-4-MeOBnE (1 mg/kg) administration for 45 days on depressive-like behavior and memory impairment in 3xTg mice, before the pathology is completely established. The treatment with QTC-4-MeOBnE prevented memory impairment and depressive-like behavior assessed by the Y-Maze task and forced swimming test. This effect was associated with the modulation of plural pathways involved in the onset and progression of AD, in cerebral structures of the cortex and hippocampus. Among them, the reduction of amyloid beta (Aβ) production mediated by changes in amyloid precursor protein metabolism and hippocampal tau phosphorylation through the inhibition of kinases. Additionally, QTC-4-MeOBnE also exerted beneficial effects on neuroinflammation and synaptic integrity. Overall, our studies suggest that QTC-4-MeOBnE has a moderate effect in a transgenic model of AD, indicating that perhaps studies regarding the neuropsychiatric effects as a neuroprotective molecule are more prone to be feasible., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The need for therapeutics to overcome development of existing diseases research to discover new lead agents. In the face of public health challenges worldwide, natural medicines play a pivotal role in innovative lead drug discovery. Network pharmacology can easily construct complicated poly-pharmacology network based on lead compound, biological function, and bioactive target proteins, which meets the overall feature of natural medicines, and enable to elucidate the action mechanism at molecule-protein level with systematic view. In this work, we first summarized the recent progress delineating lead drug development and its interaction with natural medicines. Second, we focused on the relationship between natural medicines and network pharmacology. Additionally, we discussed current issues and potential prospects for the lead drug discover from natural medicines by network pharmacology. Further investigations should be focus on relevant structural analysis for biological experiment, also the dynamic and quantitative network development. In summary, it is a rational approach for innovative lead drug discovery, and with the development of structure and biology research, this approach makes it a very powerful method for the lead molecules in a high-throughput manner from a comprehensive and powerful special multi-compound to target protein/disease poly pharmacology network., Competing Interests: Conflict of Interest The authors of the present manuscript declare no potential conflict.

Alzheimer's disease (AD) has become the fourth leading cause of death in the world. Due to its complex pathogenesis, there is still a lack of effective drug treatments. Studies have found that the metal dyshomeostasis is closely related to other pathogeneses of AD such as oxidative stress, β-amyloid protein deposits, etc. Therefore, it becomes an important target to find the appropriate metal chelating agents to regulate the metal homeostasis. At the same time, because of the complex pathogenesis, single target drugs cannot achieve good effects. Therefore, current studies are mainly focused on exploring multi-target therapy for AD. In this work, the multi-target studies based on metal chelators and other targets with synergistic anti-AD activities were reviewed. The structural characteristics of different chelating agents were summarized and the structure-activity relationship was analyzed, which provided some valuable clues for the subsequent development of anti-AD multi-target drugs based on metal chelating agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) is the main cause of dementia in older age. The prevalence of AD is growing worldwide, causing a tremendous burden to societies and families. Due to the complexity of its pathogenesis, the current treatment of AD is not satisfactory, and drugs acting on a single target may not prevent AD progression. This review summarizes the multi-target pharmacological effects of thiazolidinediones (TZDs) on AD. TZDs act as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and long-chain acyl-CoA synthetase family member 4 (ACSL4) inhibitors. TZDs ameliorated neuroinflammation and ferroptosis in preclinical models of AD. Here, we discussed recent findings from clinical trials of pioglitazone in the treatment of AD, ischemic stroke, and atherosclerosis. We also dissected the major limitations in the clinical application of pioglitazone and explained the potential benefit of pioglitazone in AD. We recommend the use of pioglitazone to prevent cognitive decline and lower AD risk in a specific group of patients.

Background: Polypharmacology means drugs having interactions with multiple targets of a unique disease or many disease pathways. This concept has been greatly appreciated against complex diseases, such as oncology, CNS disorders, and anti-infectives., Methods: The integration of diverse compounds available on public databases initiates polypharmacological drug discovery research. Immunocompromised patients may suffer from complex diseases. Multiple-component drug formulations may produce side effects and resistance issues due to unintended drug-target interactions., Results: Polypharmacology remains a novel avenue to propose a more effective and less toxic treatment. The 4-amino quinoline scaffold has become an important construction motif for the development of new drugs against lifestyle diseases like cancer and infectious diseases like tuberculosis and malaria., Conclusion: The present study is an attempt to explore the polypharmacological effects of 4- aminoquinoline drugs to combat malaria, cancer, and tuberculosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Traditional Chinese Medicine (TCM) prescriptions are organically composed of compatible herbs according to the TCM theory. The complex ingredients of TCM could act on multiple targets through various pathways simultaneously to exert pharmacological effects, making TCM an unrivaled gem in the medical world. However, due to a lack of comprehensive and standard study methods, the research of TCM products has been quite limited. A novel paradigm that could aid in the discovery of the material basis and fully clarify the mechanism of TCM prescriptions is urgently needed. In this study, a similarity analysis based on molecular fingerprints was adopted to explore the representative molecules of the Tiaoxin recipe , a Chinese patent formula approved by the National Medical Products Administration (NMPA) for the treatment of mild-to-moderate Alzheimer's disease (AD), and 38 out of 1047 chemicals were finally screened out. Next, we tried to define a new concept of a "functional molecule cluster" for chemicals with similar pharmacological effects to elucidate how the chemical mixture from TCMs produce their therapeutic effects. Four anti-AD functional molecule clusters from the Tiaoxin recipe were identified: an anti-inflammatory cluster, an anti-ROS cluster, an anti-AChE activity cluster, and an anti-A[Formula: see text] aggregation cluster. Furthermore, the chemicals from the anti-inflammatory cluster and anti-ROS cluster were proved to display their multi-target and multi-pathway roles partially or mainly through molecules of the TLR4-MYD88-NF-[Formula: see text]B and Keap1-Nrf2-ARE pathways. The functional molecule clusters may be vital to the explanation of the efficacy of the Tiaoxin recipe , which could give us a more profound understanding of TCM prescriptions. Our paradigm may open a novel path for TCM research.

An extensive study was performed to discover a series of novel 20(R)-panaxadiol derivatives with various substituents at the 3-OH position as nontoxic, brain-permeable, multi-target leads for treating Alzheimer's disease. In vitro analysis revealed that a compound bearing benzyl-substituted carbamate, which we denoted compound 14a, exhibited the most potent neuroprotective activity, with an EC 50 of 13.17 μM. The neuroprotective effect of compound 14a was slightly more potent than that of donepezil and much more potent than that of 20(R)-panaxadiol. Compound 14a at 7.5-120 μM exhibited low toxicity in various cell lines. In addition, compound 14a exhibited a wide range of biological activities, including inhibiting apoptosis; inducing tau hyperphosphorylation; affecting beta-amyloid (Aβ), β-secretase, reactive oxygen species, tumor necrosis factor-α, cyclooxygenase-2, and interleukin-1β production; and promoting Aβ 25-35 disaggregation. The effective permeability of compound 14a across the blood-brain barrier was 26.13 × 10 -6  cm/s, indicating that it can provide adequate exposure in the central nervous system. Further, compound 14a improved learning, memory, and novel object recognition in mice, and in vivo toxicity experiments confirmed a good therapeutic safety range. Thus, compound 14a is a promising multifunctional lead for treating Alzheimer's disease and offers new avenues for natural product-derived anti-Alzheimer's disease drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Polypharmacology has become a new paradigm in drug discovery and plays an increasingly vital role in discovering multi-target drugs. In this context, multi-target drugs are a promising approach to treating polygenic diseases. Many in-silico prediction methods have been developed to screen active molecules acting on multiple targets. The relationship between the action of multiple targets and the drug's overall efficacy is significant for developing multi-target drugs. So, the prediction method for this relationship urgently needs to be developed. This paper introduces multi-target-based polypharmacology prediction (mTPP), an approach using virtual screening and machine learning to explore the relationship. To predict the activity of the potential hepatoprotective components, the data on the binding strength of a single ingredient with multiple targets and the proliferation rate of the compounds against acetaminophen (APAP)-induced injury L02 cells were all used to construct the mTPP model by Multi-layer Perceptron (MLP), Support Vactor Regression (SVR), Decision Tree Regressor (DTR), and Gradient Boost Regression (GBR) algorithms. Compared with MLP, SVR, and DTR algorithms, GBR algorithms showed the best performance with R 2 test  = 0.75. In addition, 20 candidates with potential effects against drug-induced liver injury (DILI) were predicted by the mTPP model. Furthermore, 2 of the 20 candidates, Chelerythrine and Biochanin A, were applied to evaluate the model's accuracy. The results showed that Chelerythrine and Biochanin A could improve the viability of APAP-induced injury cells. Thus, the mTPP model is hoped to help develop polypharmacology and discover multi-target drugs.test  = 0.75. In addition, 20 candidates with potential effects against drug-induced liver injury (DILI) were predicted by the mTPP model. Furthermore, 2 of the 20 candidates, Chelerythrine and Biochanin A, were applied to evaluate the model's accuracy. The results showed that Chelerythrine and Biochanin A could improve the viability of APAP-induced injury cells. Thus, the mTPP model is hoped to help develop polypharmacology and discover multi-target drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

COVID-19 is a progressing pandemic of coronavirus disease-2019, which had drowned the whole world in a deep sorrow sea. Uncountable deaths were extending the list of deaths every single day. The present research was aimed to study the multi-target interaction of coumarins against COVID-19 using molecular docking analysis. The structure of coumarin compounds was checked for ADME and Lipinski rule of five by using SwissADME, an online tool. SARS-CoV-2 proteins such as RdRp, PLpro, Mpro and spike protein were collected from the Protein Data Bank. The molecular docking study was performed in the PyRx tool, and the molecular interactions were visualised by Discovery Studio Visualizer. All the coumarin compounds used in the study were obeyed Lipinski's rule of 5 without any violations. All the three designed derivatives of phenprocoumon, hymecromone, and psoralen were showed high binding affinity and prominent interactions with the drug target. The presence of -OH groups in the compound, His41, a catalytic dyad in Mpro, number of and the distance of hydrogen bond interactions with SARS-CoV-2 targets was accountable for the high binding attractions. The modified drug structures possess better binding efficacy towards at least three targets compared to their parent compounds. Further, molecular dynamic studies can be suggested to find the ligand-protein complex stability. The present study outcome reveals that the designed coumarins can be synthesised and examined as a potent inhibitory drug of SARS-CoV-2., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease. Acetylcholinesterase inhibitors (AChEIs) are a major class of drugs used in AD therapy. ROCK2, another promising target for AD, has been associated with the induction of neurogenesis via PTEN/AKT. This study aimed to characterize the therapeutic potential of a novel donepezil-tacrine hybrid compound (TA8Amino) to inhibit AChE and ROCK2 protein, leading to the induction of neurogenesis in SH-SY5Y cells. Experiments were carried out with undifferentiated and neuron-differentiated SH-SY5Y cells submitted to treatments with AChEIs (TA8Amino, donepezil, and tacrine) for 24 h or 7 days. TA8Amino was capable of inhibiting AChE at non-cytotoxic concentrations after 24 h. Following neuronal differentiation for 7 days, TA8Amino and donepezil increased the percentage of neurodifferentiated cells and the length of neurites, as confirmed by β-III-tubulin and MAP2 protein expression. TA8Amino was found to participate in the activation of PTEN/AKT signaling. In silico analysis showed that TA8Amino can stably bind to the active site of ROCK2, and in vitro experiments in SH-SY5Y cells demonstrate that TA8Amino significantly reduced the expression of ROCK2 protein, contrasting with donepezil and tacrine. Therefore, these results provide important information on the mechanism underlying the action of TA8Amino with regard to multi-target activities.

Curcumin (aglycone curcumin) has antitumor properties in a variety of malignancies via the alteration of multiple cancer-related biological pathways; however, its clinical application has been hampered due to its poor bioavailability. To overcome this limitation, we have developed a synthesized curcumin β-D-glucuronide sodium salt (TBP1901), a prodrug form of aglycone curcumin. In this study, we aimed to clarify the pharmacologic characteristics of TBP1901. In β-glucuronidase (GUSB)-proficient mice, both curcumin β-D-glucuronide and its active metabolite, aglycone curcumin, were detected in the blood after TBP1901 injection, whereas only curcumin β-D-glucuronide was detected in GUSB-impaired mice, suggesting that GUSB plays a pivotal role in the conversion of TBP1901 into aglycone curcumin in vivo. TBP1901 itself had minimal antitumor effects in vitro, whereas it demonstrated significant antitumor effects in vivo. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screen disclosed the genes associated with NF-κB signaling pathway and mitochondria were among the highest hit. In vitro, aglycone curcumin inhibited NF-kappa B signaling pathways whereas it caused production of reactive oxygen species (ROS). ROS scavenger, N-acetyl-L-cysteine, partially reversed antitumor effects of aglycone curcumin. In summary, TBP1901 can exert antitumor effects as a prodrug of aglycone curcumin through GUSB-dependent activation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tadashi Hashimoto is the chief executive officer of Therabiopharma Inc. Atushi Imaizumi is the senior vice president of Therabiopharma Inc. Tomoyuki Abe, Hitomi Ozawa-Umeta, Atsuhiro Kishimoto, and Yasuhiro Katsuura are employees of Therabiopharma Inc. Masashi Kanai. and Hideaki Kakeya own equity and they are the scientific consultants of Therabiopharma Inc., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Liver X receptors (LXRs) are important regulators of cholesterol metabolism and inflammatory responses. LXR agonists exhibit potently anti-inflammatory effects in macrophages, which make them beneficial to anti-atherogenic therapy. In addition to transrepressive regulation by SUMOylation, LXRs can inhibit inflammation by various mechanisms through affecting multiple targets. In this study, we found that the classic LXR agonist T0901317 mediated numerous genes containing alternative splice sites, including myeloid differentiation factor 88 (MyD88), that contribute to inflammatory inhibition in RAW264.7 macrophages. Furthermore, T0901317 increased level of alternative splice short form of MyD88 mRNA by down-regulating expression of splicing factor SF3A1, leading to nuclear factor κB-mediated inhibition of inflammation. In conclusion, our results suggest for the first time that the LXR agonist T0901317 inhibits lipopolysaccharide-induced inflammation through regulating MyD88 mRNA alternative splicing involved in TLR4 signaling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Li, Han, Zhang, Han, Jiang, Wang, Xu, Xu, Fu and Si.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections generate approximately one million virions per day, and the majority of available antivirals are ineffective against it due to the virus's inherent genetic mutability. This necessitates the investigation of concurrent inhibition of multiple SARS-CoV-2 targets. We show that fortunellin (acacetin 7-O-neohesperidoside), a phytochemical, is a promising candidate for preventing and treating coronavirus disease (COVID-19) by targeting multiple key viral target proteins. Fortunellin supports protective immunity while inhibiting pro-inflammatory cytokines and apoptosis pathways and protecting against tissue damage. Fortunellin is a phytochemical found in Gojihwadi kwath, an Indian traditional Ayurvedic formulation with an antiviral activity that is effective in COVID-19 patients. The mechanistic action of its antiviral activity, however, is unknown. The current study comprehensively evaluates the potential therapeutic mechanisms of fortunellin in preventing and treating COVID-19. We have used molecular docking, molecular dynamics simulations, free-energy calculations, host target mining of fortunellin, gene ontology enrichment, pathway analyses, and protein-protein interaction analysis. We discovered that fortunellin reliably binds to key targets that are necessary for viral replication, growth, invasion, and infectivity including Nucleocapsid (N-CTD) (-54.62 kcal/mol), Replicase-monomer at NSP-8 binding site (-34.48 kcal/mol), Replicase-dimer interface (-31.29 kcal/mol), Helicase (-30.02 kcal/mol), Papain-like-protease (-28.12 kcal/mol), 2'-O-methyltransferase (-23.17 kcal/mol), Main-protease (-21.63 kcal/mol), Replicase-monomer at dimer interface (-22.04 kcal/mol), RNA-dependent-RNA-polymerase (-19.98 kcal/mol), Nucleocapsid-NTD (-16.92 kcal/mol), and Endoribonuclease (-16.81 kcal/mol). Furthermore, we identify and evaluate the potential human targets of fortunellin and its effect on the SARS-CoV-2 infected tissues, including normal-human-bronchial-epithelium (NHBE) and lung cells and organoids such as pancreatic, colon, liver, and cornea using a network pharmacology approach. Thus, our findings indicate that fortunellin has a dual role; multi-target antiviral activities against SARS-CoV-2 and immunomodulatory capabilities against the host., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Multi-agent therapies are an important treatment modality in many diseases based on the assumption that combining agents may result in increased therapeutic benefit by overcoming the mechanism of resistance and providing superior efficiency. Extensively validated 3D pharmacophore models for free fatty acid receptor-1 (FFAR-1), free fatty acid receptor-4 (FFAR-4), and peroxisome proliferator-activated receptor-G (PPAR-G) was developed. The pharmacophore model for FFAR-1 ( r 2 = 0.98, q 2 = 0.90) and PPAR-G ( r 2 = 0.89, q 2 = 0.88) suggested that one hydrogen bond acceptor, one hydrogen bond donor, three aromatic rings, and two hydrophobic groups arranged in 3D space are essential for the binding affinity of FFAR-1 and PPAR-G inhibitors. Similarly, the pharmacophore model for FFAR-4 ( r 2 = 0.92, q 2 = 0.87) suggested that the presence of a hydrogen bond acceptor, one negative atom, two aromatic rings, and three hydrophobic groups plays a vital role in the binding of an inhibitor of FFAR-4. These pharmacophore models allowed searches for novel FFAR-1, PPAR-G, and FFAR-4 triple inhibitors from multi-conformer 3D databases (Asinex). Finally, the twenty-five best hits were selected for molecular docking, to study the interaction of their complexes with all the proteins and final binding orientations of these molecules. After molecular docking, ten hits have been predicted to possess good binding affinity as per the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) calculation for FFAR-1, FFAR-4, and PPAR-G which can be further investigated for its experimental in-vitro / in-vivo anti-diabetic activities.Communicated by Ramaswamy H. Sarma.

The apoptotic antiproliferative actions of our previously reported CB1 allosteric modulators 5-chlorobenzofuran-2-carboxamide derivatives VIIa - j prompted us to develop and synthesise a novel series of indole-2-carboxamide derivatives 5a - k , 6a - c , and 7 . Different spectroscopic methods of analysis were used to validate the novel compounds. Using the MTT assay method, the novel compounds were examined for antiproliferative activity against four distinct cancer cell lines. Compounds 5a - k , 6a - c , and 7 demonstrated greater antiproliferative activity against the breast cancer cell line (MCF-7) than other tested cancer cell lines, and 5a - k (which contain the phenethyl moiety in their backbone structure) demonstrated greater potency than 6a - c and 7 , indicating the importance of the phenethyl moiety for antiproliferative action. Compared to reference doxorubicin (GI 50 = 1.10 µM), compounds 5d , 5e , 5h , 5i , 5j , and 5k were the most effective of the synthesised derivatives, with GI 50 ranging from 0.95 µM to 1.50 µM. Compounds 5d , 5e , 5h , 5i , 5j , and 5k were tested for their inhibitory impact on EGFR and CDK2, and the results indicated that the compounds tested had strong antiproliferative activity and are effective at suppressing both CDK2 and EGFR. Moreover, the studied compounds induced apoptosis with high potency, as evidenced by their effects on apoptotic markers such as Caspases 3, 8, 9, Cytochrome C, Bax, Bcl2, and p53.