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Introduction: Chronic cocaine exposure induces an increase in dopamine release and an increase in the expression of the Fos protein in the rat striatum. It has been suggested that both are necessary for the expression of cocaine-induced alterations in behavior and neural circuitry. Mirtazapine dosing attenuated the cocaine-induced psychomotor and reinforcer effects. Methods: The study evaluates the effect of chronic dosing of mirtazapine on cocaine-induced extracellular dopamine levels and Fos protein expression in rats. Male Wistar rats received cocaine (10 mg/Kg; i.p.) during the induction and expression of locomotor sensitization. The mirtazapine (30 mg/Kg; MIR), was administered 30 minutes before cocaine during the cocaine withdrawal. After each treatment, the locomotor activity was recorded for 30 minutes. Animals were sacrificed after treatment administration. Dopamine levels were determined by high-performance liquid chromatographic (HPLC) in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) in animals treated with mirtazapine and cocaine. The quantification of c-fos immunoreactive cells was carried out by stereology analysis. Results: Mirtazapine generated a decrease in cocaine-induced locomotor activity. In addition, mirtazapine decreased the amount of cocaine-induced dopamine and the number of cells immunoreactive to the Fos protein in the striatum, PFC, and VTA. Discussion: These data suggest that mirtazapine could prevent the consolidation of changes in behavior and the cocaine-induced reorganization of neuronal circuits. It would explain the mirtazapine-induced effects on cocaine behavioral sensitization. Thus, these data together could support its possible use for the treatment of patients with cocaine use disorder.

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Alzheimer's disease (AD), a leading cause of dementia, increasingly challenges our healthcare systems and society. Traditional therapies aimed at single targets have fallen short owing to the complex, multifactorial nature of AD that necessitates simultaneous targeting of various disease mechanisms for clinical success. Therefore, targeting multiple pathologies at the same time could provide a synergistic therapeutic effect. The identification of new disease targets beyond the classical hallmarks of AD offers a fertile ground for the design of new multi-target drugs (MTDs), and building on existing compounds have the potential to yield in successful disease modifying therapies. This review discusses the evolving landscape of MTDs, focusing on their potential as AD therapeutics. Analysis of past and current trials of compounds with multi-target activity underscores the capacity of MTDs to offer synergistic therapeutic effects, and the flourishing genetic understanding of AD will inform and inspire the development of MTD-based AD therapies.

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Cancer is a major public health problem worldwide with more than an estimated 19.3 million new cases in 2020. The occurrence rises dramatically with age, and the overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective in older individuals. Conventional cancer treatments, such as radiotherapy, surgery, and chemotherapy, have been used for decades to combat cancer. However, the emergence of novel fields of cancer research has led to the exploration of innovative treatment approaches focused on immunotherapy, epigenetic therapy, targeted therapy, multi-omics, and also multi-target therapy. The hypothesis was based on that drugs designed to act against individual targets cannot usually battle multigenic diseases like cancer. Multi-target therapies, either in combination or sequential order, have been recommended to combat acquired and intrinsic resistance to anti-cancer treatments. Several studies focused on multi-targeting treatments due to their advantages include; overcoming clonal heterogeneity, lower risk of multi-drug resistance (MDR), decreased drug toxicity, and thereby lower side effects. In this study, we'll discuss about multi-target drugs, their benefits in improving cancer treatments, and recent advances in the field of multi-targeted drugs. Also, we will study the research that performed clinical trials using multi-target therapeutic agents for cancer treatment.

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The global pandemic of type 2 diabetes mellitus is still ongoing, in which obesity has played a major role. Obesity not only contributes to the development of type 2 diabetes but also further increases the risk of cardiovascular diseases in patients with type 2 diabetes. In recent years, the management goals of diabetes care has shifted from glycemic control alone to dual " glycemic control and weight loss". Current weight loss strategies include lifestyle intervention, pharmacotherapy therapy, and metabolic surgery, with advancements being made particularly in pharmacological treatments. The novel dual or triple gut hormone receptor agonists hold promise for providing more treatment options for overweight/obese patients with type 2 diabetes.

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Caffeoylquinic acids (CQA) are polyphenolic compounds found in fruits, vegetables, coffee, and spices that have exhibited several beneficial activities, including antioxidant, antibacterial, neuroprotective, anti-inflammatory, anticancer, antiviral, antidiabetic, and cardiovascular effects. A derivative, TCQA (3,4,5-Tri-O-caffeoylquinic acid), has also shown both neurogenic and pigment differentiation potential. A transcriptomic-based meta-analysis was conducted to explore potential biochemical processes and molecular targets of TCQA. This approach involved integrating data from various cell and tissue types, including human amniotic stem cells, human neural stem cells, human dermal papilla cells, and the brain cortex of aging model mice. It offered a comprehensive perspective on the significant gene regulations in response to TCQA treatment. The objective was to uncover the mechanism and novel targets of TCQA, facilitating a further understanding of its functions. New areas of interest found were TCQA's effect on adipogenesis, heart, and muscle tissue development. In addition, significantly enhanced biological activities found through meta-analysis included cell cycle, VEGFA-VEGFR2 pathway, and BMP signaling. Overall, a comprehensive functional and visual analysis using available biological databases uncovered the multi-target potential of this natural compound.

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Polypharmacology is an emerging strategy of design, synthesis, and clinical implementation of pharmaceutical agents that act on multiple targets simultaneously. It should not be mixed up with polytherapy, which is based on the use of multiple selective drugs and is considered a cornerstone of current clinical practice. However, this 'classic' approach, when facing urgent medical challenges, such as multifactorial diseases, increasing resistance to pharmacotherapy, and multimorbidity, seems to be insufficient. The 'novel' polypharmacology concept leads to a more predictable pharmacokinetic profile of multi-target-directed ligands (MTDLs), giving a chance to avoid drug-drug interactions and improve patient compliance due to the simplification of dosing regimens. Plenty of recently marketed drugs interact with multiple biological targets or disease pathways. Many offer a significant additional benefit compared to the standard treatment regimens. In this paper, we will briefly outline the genesis of polypharmacology and its differences to polytherapy. We will also present leading concepts for obtaining MTDLs. Subsequently, we will describe some successfully marketed drugs, the mechanisms of action of which are based on the interaction with multiple targets. To get an idea, of whether MTDLs are indeed important in contemporary pharmacology, we also carefully analyzed drugs approved in 2022 in Germany: 10 out of them were found multi-targeting, including 7 antitumor agents, 1 antidepressant, 1 hypnotic, and 1 drug indicated for eye disease.

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The majority of research to combat SARS-CoV-2 infection exploits the adaptive immune system, but innate immunity, the first line of defense against pathogenic microbes, is equally important in understanding and controlling infectious diseases. Various cellular mechanisms provide physiochemical barriers to microbe infection in mucosal membranes and epithelia, with extracellular polysaccharides, particularly sulfated polysaccharides, being among the most widespread and potent extracellular and secreted molecules blocking and deactivating bacteria, fungi, and viruses. New research reveals that a range of polysaccharides effectively inhibits COV-2 infection of mammalian cells in culture. This review provides an overview of sulfated polysaccharides nomenclature, its significance as immunomodulators, antioxidants, antitumors, anticoagulants, antibacterial, and as potent antivirals. It summarizes current research on various interactions of sulfated polysaccharide with a range of viruses, including SARS-CoV-2, and their application for potential treatments for COVID-19. These molecules interact with biochemical signaling in immune cell responses, by actions in oxidative reactions, cytokine signaling, receptor binding, and through antiviral and antibacterial toxicity. These properties provide the potential for the development of novel therapeutic treatments for SARS-CoV-2 and other infectious diseases from modified polysaccharides.

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Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities.

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Cancer care has become a challenge with the current COVID-19 pandemic scenario. Specially, cancers like small cell lung cancers (SCLC) are difficult to treat even in the normal situation due to their rapid growth and early metastasis. For such patients, treatment can't be compromised and care must be taken to ensure their minimum exposure to the ongoing spread of COVID-19 infection. For this reason, in-house treatments are being suggested for these patients. Another issue is that symptoms of SCLC match well with that of COVID-19 infection. Hence, the detection of COVID-19 may also get delayed leading to unnecessary complications. Thus, we have tried to investigate if the therapeutics that is currently used in lung cancer treatment can also act against SARS-CoV-2. If it is so, the same treatment protocols can be continued even if the SCLC patient had contracted COVID-19 without compromising the cancer care. For this, RNA dependent RNA polymerase (RdRP) from SARS-CoV-2 has been selected as drug target. Both docking and molecular dynamicssimulation analysis have indicated that Paclitaxel and Dacomitinib may be explored as multi-target drugs for both SCLC and COVID-19.Communicated by Ramaswamy H. Sarma.

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The heterogeneity of tumor microenvironment leads to uneven distribution of bio-stimuli. Thus, the multi-site delivery efficiency of responsive drug delivery systems (DDS) inner tumor was always limited. Herein, we proposed a combination strategy of photodynamic therapy (PDT) with ROS-responsive nanosystem which was constructed from dextran-phenylboronic acid pinacol ester conjugates. This combination utilized PDT to amplify and homogenize tissular oxidation level, and achieve effective multi-site response and release of multi-target drugs like gambogic acid (GA). Our research demonstrated the successful preparation of GA and protoporphyrin IX (PpIX) co-loaded nanoparticles, and the PDT-mediated spatiotemporal controlled multi-site drug release in simulated conditions. Furthermore, data from in vitro and in vivo researches on B16F10 cells, HUVEC, and B16F10-bearing C57BL/6 mice potently confirmed the enhanced multi-mechanism regulations of GA mediated by the effective and homogeneous tumoral release. This tactic based on bio-stimuli amplification and homogenization proposes a paradigm to maximize the potency of multi-target drugs.

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There is new and increasing evidence from in vitro, in vivo and clinical studies implicating the pivotal role of iron and associated metabolic pathways in the initiation, progression and development of cancer and in cancer metastasis. New metabolic and toxicity mechanisms and pathways, as well as genomic, transcription and other factors, have been linked to cancer and many are related to iron. Accordingly, a number of new targets for iron chelators have been identified and characterized in new anticancer strategies, in addition to the classical restriction of/reduction in iron supply, the inhibition of transferrin iron delivery, the inhibition of ribonucleotide reductase in DNA synthesis and high antioxidant potential. The new targets include the removal of excess iron from iron-laden macrophages, which affects anticancer activity; the modulation of ferroptosis; ferritin iron removal and the control of hyperferritinemia; the inhibition of hypoxia related to the role of hypoxia-inducible factor (HIF); modulation of the function of new molecular species such as STEAP4 metalloreductase and the metastasis suppressor N-MYC downstream-regulated gene-1 (NDRG1); modulation of the metabolic pathways of oxidative stress damage affecting mitochondrial function, etc. Many of these new, but also previously known associated iron metabolic pathways appear to affect all stages of cancer, as well as metastasis and drug resistance. Iron-chelating drugs and especially deferiprone (L1), has been shown in many recent studies to fulfill the role of multi-target anticancer drug linked to the above and also other iron targets, and has been proposed for phase II trials in cancer patients. In contrast, lipophilic chelators and their iron complexes are proposed for the induction of ferroptosis in some refractory or recurring tumors in drug resistance and metastasis where effective treatments are absent. There is a need to readdress cancer therapy and include therapeutic strategies targeting multifactorial processes, including the application of multi-targeting drugs involving iron chelators and iron-chelator complexes. New therapeutic protocols including drug combinations with L1 and other chelating drugs could increase anticancer activity, decrease drug resistance and metastasis, improve treatments, reduce toxicity and increase overall survival in cancer patients.

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Alzheimer's disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV-BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid ß-peptide (Aß) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aß42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9-1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1-58.7%) and Cu(II)-induced (40.3-60.8%) Aß aggregation and also to narrow (22.4-42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aß42 and oxidative stress. Therefore, RIV-BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.

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INTRODUCTION: Current findings on multifactorial diseases with a complex pathomechanism confirm that multi-target drugs are more efficient ways in treating them as opposed to single-target drugs. However, to design multi-target ligands, a number of factors and challenges must be taken into account. AREAS COVERED: In this perspective, we summarize the concept of application of multi-target drugs for the treatment of complex diseases such as neurodegenerative diseases, schizophrenia, diabetes, and cancer. We discuss the aspects of target selection for multifunctional ligands and the application of in silico methods in their design and optimization. Furthermore, we highlight other challenges such as balancing affinities to different targets and drug-likeness of obtained compounds. Finally, we present success stories in the design of multi-target ligands for the treatment of common complex diseases. EXPERT OPINION: Despite numerous challenges resulting from the design of multi-target ligands, these efforts are worth making. Appropriate target selection, activity balancing, and ligand drug-likeness belong to key aspects in the design of ligands acting on multiple targets. It should be emphasized that in silico methods, in particular inverse docking, pharmacophore modeling, machine learning methods and approaches derived from network pharmacology are valuable tools for the design of multi-target drugs.

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Aim: The aim of the study is to compare the efficacy and safety of monotherapy with a sequential immune checkpoint inhibitor (ICI) programmed cell death protein-1 (PD-1) and its combination with multi-target drug sorafenib after transcatheter arterial chemoembolization (TACE) for advanced hepatocellular carcinoma (HCC). Methods: We conducted a retrospective evaluation of patients with advanced HCC who had received sequential PD-1 sorafenib (duplex group, n = 25) or monotherapy PD-1 alone (PD-1 group, n = 41) after TACE during April 2018-September 2021. Propensity score matching (PSM) was applied to correct the selection bias, and 22 pairs were created. The objective response rate (ORR), duration of the overall response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events were analyzed for both groups. Results: After PSM, the median PFS (7.63 vs. 2.9 months; p = 0.0335) was significantly longer for the duplex group than for the PD-1 group. The median OS (21.63 vs. 16.43 months; p = 0.103) was longer for the duplex group than for the PD-1 group, albeit without any statistical difference. The CR rate, ORR, DCR, and PFS rates at the first, third, and sixth months were higher for the duplex group than for the PD-1 group, wherein the PFS rate of the third and sixth months were statistically different. The OS rates at the sixth, 12th, and 18th months were better for the duplex group than for the PD-1 group, while the 18th-month OS rate (54.5% vs. 33.9%, p = 0.030) were statistically different between them. The most common adverse events after TACE included liver function injury, leukocytopenia, and thrombocytopenia, albeit without any statistical differences between the groups. Cox regression analysis showed that sorafenib combined immunotherapy after TACE and the achieving of CR or PR during the treatment were independent factors affecting PFS. Moreover, CNLC stage-IIIa, TACE frequency ≤2, and achievement of CR or PR were independent influencing factors of OS. Conclusions: Sequential PD-1 combined with sorafenib therapy after TACE for advanced HCC treatment is safe and effective, especially for patients with good initial treatment response, to further improve the disease prognosis.

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Cardiovascular diseases (CVDs) comprise a group of diseases and disorders of the heart and blood vessels, which together are the number one cause of death worldwide, being associated with multiple genetic and modifiable risk factors, and that may directly arise from different etiologies. For a long time, the search for cardiovascular drugs was based on the old paradigm "one compound - one target", aiming to obtain a highly potent and selective molecule with only one desired molecular target. Although historically successful in the last decades, this approach ignores the multiple causes and the multifactorial nature of CVDs. Thus, over time, treatment strategies for cardiovascular diseases have changed, and, currently, pharmacological therapies for CVD are mainly based on the association of two or more drugs to control symptoms and reduce cardiovascular death. In this context, the development of multitarget drugs, i.e., compounds having the ability to act simultaneously at multiple sites, is an attractive and relevant strategy that can be even more advantageous to achieve predictable pharmacokinetic and pharmacodynamics correlations as well as better patient compliance. In this review, we aim to highlight the efforts and rational pharmacological bases for the design of some promising multitargeted compounds to treat important cardiovascular diseases like heart failure, atherosclerosis, acute myocardial infarction, pulmonary arterial hypertension, and arrhythmia.

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Giving the fact that the disorders of multiple receptor tyrosine kinases (RTKs) are characteristics of various cancers, we assumed that developing novel multi-target drugs might have an advantage in treating the complex cancers. Taking the multi-target c-Met inhibitor Foretinib as the leading compound, we discovered a novel series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety with the help of molecular docking. Among them, the most promising compound 33 showed a prominent activity against Hela (IC50 = 0.21 µM), A549 (IC50 = 0.39 µM), and MCF-7 (IC50 = 0.33 µM), which were 3.28-4.82 times more active than that of Foretinib. Additionally, compound 33 dose dependently induced apoptosis by arresting A549 cells at G1 phase. Enzymatic assays and docking analyses were further confirmed that compound 33 was a multi-target inhibitor with the strong potencies against c-Met (IC50 = 11.77 nM), MEK1 (IC50 = 10.71 nM), and Flt-3 (IC50 = 22.36 nM). In the A549 cells mediated xenograft mouse model, compound 33 inhibited the tumor growth (TGI = 64%) without obvious toxicity, establishing compound 33 as a promising candidate for cancer therapy.

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Despite the ever-increasing number of available options for the treatment of epilepsies and the remarkable advances on the understanding of their pathophysiology, the proportion of refractory patients has remained approximately unmodified during the last 100 years. How efficient are we translating positive outcomes from basic research to clinical trials and/or the clinical scenario? It is possible that fresh thinking and exploration of new paradigms are required to arrive at truly novel therapeutic solutions, as seemingly proven by recently approved first-in-class antiseizure medications and drug candidates undergoing late clinical trials. Here, the author discusses some approximations in line with the network pharmacology philosophy, which may result in highly innovative (and, hopefully, safer and/or more efficacious) medications for the control of seizures, as embodied with some recent examples in the field, namely tailored multi-target agents and low-affinity ligands.

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Background: Drug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease. Methods: Here, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of in vitro (EC50 = 0.4 µM) and in vivo models, we show that methotrexate is able to inhibit COVID-19 via multiple mechanisms. Results: Our in vitro studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals. Conclusions: We demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials.

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Ten acridones isolated from Atalantia monophylla were evaluated for effects on Alzheimer's disease pathogenesis including antioxidant effects, acetylcholinesterase (AChE) inhibition, prevention of beta-amyloid (Aß) aggregation and neuroprotection. To understand the mechanism, the type of AChE inhibition was investigated in vitro and binding interactions between acridones and AChE or Aß were explored in silico. Drug-likeness and ADMET parameters were predicted in silico using SwissADME and pKCSM programs, respectively. All acridones showed favorable drug-likeness and possessed multifunctional activities targeting AChE function, Aß aggregation and oxidation. All acridones inhibited AChE in a mixed-type manner and bound AChE at both catalytic anionic and peripheral anionic sites. In silico analysis showed that acridones interfered with Aß aggregation by interacting at the central hydrophobic core, C-terminal hydrophobic region, and the key residues 41 and 42. Citrusinine II showed potent multifunctional action with the best ADMET profile and could alleviate neuronal cell damage induced by hydrogen peroxide and Aß1-42 toxicity.