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Combinations of drugs have demonstrated potential therapeutic results in controlling the progression of cancer, with a possible decrease in toxicity and unfavorable side efects. Experimental screening is no longer feasible due to the vast number of possible medication combinations. As a result, the scientific community is becoming more and more interested in creating computational models that can quickly and precisely identify prospective drug combinations. Our methodology employs therapeutically significant drugs and cell line properties in machine learning techniques. Our suggested stacked machine learning model outperforms all other machine learning models taken into consideration. It employs Random Forest and XGBoost as base learners and Logistic Regression as a meta learner. The results of our research underscore the remarkable efficacy of our approach. Not only does it address the complexities of the task at hand, but it also showcases its potential to enhance predictive accuracy within this domain. The comparative analysis reveals that our model exhibits a noteworthy performance improvement across multiple evaluation metrics. Our findings represent a significant step forward in the quest for improved cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine. [Display omitted] • A dynamic proteomic landscape under the treatment of 78 bioactive compounds. • The integrative analysis showing the connectivity between MOA and proteomics. • Functional relevance indicating the novel and "off-target" pharmacological active. • Uncovering the drug combination of histone methyltransferase and topoisomerase. [ABSTRACT FROM AUTHOR]

Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents. To overcome it, the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier. Herein, a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound. In this proof-of-concept study, the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1 (XPO1) and ataxia telangiectasia mutated-Rad3-related (ATR), and then a super-assembled nano-pill (gold nano drug carrier loaded AZD6738 and 97−110 amino acids of apoptin (AP) (AA@G)) was constructed through camouflaging AZD6738 (ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle. As expected, both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest, promoting DNA damage and inhibiting DNA repair of hepatoma cell. This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential, but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds, thereby extending the scope of drugs for developing the advanced combination therapy. [Display omitted] • Unified the pharmacokinetics of a peptide and a small molecular compound for intensive liver cancer treatment. • Provided a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential. • Extended the scope of drugs for developing the advanced combination therapy. [ABSTRACT FROM AUTHOR]

Conventional chemotherapy medications are inadequate for managing the primary or acquired drug resistance, high toxicity, and adverse effects of colorectal cancer (CRC) treatment. Ursolic acid (UA) and Solasodine (Sol) are natural compounds found in a wide variety of traditional medicinal plants, as well as in many fruits and vegetables, such as Actinidia arguta (Sieb. & Zucc) Planch and Solanum nigrum L.. These compounds exhibit significant anti-tumor activity. Recent investigations have demonstrated that a combination strategy using natural products exhibits greater potential in CRC treatment compared to a single-drug strategy. This study aimed to elucidate the potential of UA-Sol synergy against CRC and to investigate the mechanism of action involved in inducing apoptosis and inhibiting metastasis through the AKT1/ERK1/2-GSK-3 β - β -catenin axis. The optimal ratio of UA-Sol and its synergistic effects were explored using an MTT assay combined with the technique of Chou Talalay. The effects of UA-Sol on the apoptosis, autophagy, and metastasis of CRC cells were assessed using Annexin V-FITC/PI, TUNEL, Immunofluorescence, Wound healing, Transwell migration, and western blotting. The core mechanism of action of UA-Sol against CRC was investigated employing network pharmacology prediction combined with CETSA and plasmid transfection. Finally, in vivo validation was conducted using mouse xenograft tumor and lung metastasis models. The combination of UA and Sol synergistically inhibited CRC cell viability at a molar ratio of 6:24. UA-Sol induced the expression of pro-apoptotic and autophagy genes such as Bax/Bcl-2 and LC3, ultimately leading to apoptosis and autophagy in CRC cells in vitro. In addition, this combination inhibited MMP-9 and promoted the expression of the adhesion protein E-cadherin, thereby inhibiting CRC cell metastasis. Mechanistically, UA-Sol regulated the expression of a downstream protein GSK-3 β by targeting AKT1 and ERK1/2 inhibition. This induced a cross-talk between the MAPK cascade pathway and the PI3K/AKT pathway, thereby inhibiting the nuclear translocation of β -catenin and participating in the regulation of CRC cell processes. UA-Sol inhibited the AKT1/ERK1/2-GSK-3 β - β -catenin axis to induce apoptosis, autophagy and anti-metastasis by targeting AKT1 and ERK1/2 inhibition. This dual-target drug combination strategy provides promising insights into the development of novel, safe, and efficient drugs for the treatment of CRC. [ABSTRACT FROM AUTHOR]

Modern lifestyle has led to an increase in the incidence of obesity as a public health concern; however, current anti-obesity medications often show limited efficacy with severe side effects. Therapeutic drugs that are selectively delivered to adipose tissue and accelerate energy consumption are promising strategies to overcome the limitations of existing anti-obesity treatment approaches. Herein, a drug delivery platform based on a macrophage cell membrane (Ma)-camouflaged recombinant high-density lipoprotein (rHDL) that was further decorated with a P3 peptide was fabricated to realize targeted drug delivery to adipose tissue. By co-delivering rosiglitazone (Rosi), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, and sildenafil (Sild), a phosphodiesterase type 5 (PDE5) inhibitor, a synergistic therapeutic outcome was achieved in the regulation of diet-induced obesity in a mice model. Body weight reduction and the metabolic status of obese mice were significantly improved after 28 days of treatment. More importantly, a sustainable self-reinforcement effect in multidose therapy was found after using this delivery system. The continuous treatment increased prohibitin (PHB) expression and capillary density in adipose tissue, which in turn improved the accumulation of the drugs in subsequent administration. Taken together, this constructed drug delivery system showed high effectiveness with good safety by combining two anti-obesity therapeutic agents, which exhibits promising research potential for adipose-targeted delivery. Therapeutic strategies that directly target adipose tissue to increase energy consumption and regulate metabolism are promising but challenging. Herein, an adipose tissue-targeted delivery system was developed using a reconstituted high-density lipoprotein (rHDL) coated by a P3 peptide-decorated macrophage membrane. For the first time, we combined rosiglitazone (Rosi) and sildenafil (Sild) in the system and achieved synergy of adipose browning and angiogenesis for anti-obesity treatment. The therapy induced prohibitin expression and angiogenesis, which improved drug accumulation in adipose tissue in subsequent administrations. This resulted in a sustainable self-reinforcement effect with improved capacity for diet-induced obesity regulation. This study highlights the combination of adipose browning and angiogenesis in anti-obesity treatment and provides an innovative concept of enhancing adipose-targeted delivery. [Display omitted] [ABSTRACT FROM AUTHOR]

Medication is a major determinant of human gut microbiome structure, and its overuse increases the risks of morbidity and mortality. However, effects of certain commonly prescribed drugs and multiple medications on the gut microbiome are still underinvestigated. We performed shotgun metagenomic analysis of fecal samples from 4198 individuals in the Japanese 4D (Disease, Drug, Diet, Daily life) microbiome project. A total of 759 drugs were profiled, and other metadata, such as anthropometrics, lifestyles, diets, physical activities, and diseases, were prospectively collected. Second fecal samples were collected from 243 individuals to assess the effects of drug initiation and discontinuation on the microbiome. We found that numerous drugs across different treatment categories influence the microbiome; more than 70% of the drugs we profiled had not been examined before. Individuals exposed to multiple drugs, polypharmacy, showed distinct gut microbiome structures harboring significantly more abundant upper gastrointestinal species and several nosocomial pathobionts due to additive drug effects. Polypharmacy was also associated with microbial functions, including the reduction of short-chain fatty acid metabolism and increased bacterial stress responses. Even nonantibiotic drugs were significantly correlated with an increased antimicrobial resistance potential through polypharmacy. Notably, a 2-time points dataset revealed the alteration and recovery of the microbiome in response to drug initiation and cessation, corroborating the observed drug-microbe associations in the cross-sectional cohort. Our large-scale metagenomics unravels extensive and disruptive impacts of individual and multiple drug exposures on the human gut microbiome, providing a drug-microbe catalog as a basis for a deeper understanding of the role of the microbiome in drug efficacy and toxicity. [Display omitted] This population-level metagenomic analysis reveals extensive effects of various drugs and multiple medications on the gut microbiome. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein (P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5- a ]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp, WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel (PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4 (CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft (PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy. Preclinical studies reveal that WS-716 is a highly potent, specific and orally active P-glycoprotein inhibitor and increases sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Chinese herbal extract lycorine combined with cisplatin has synergistic anti-osteosarcoma effects. • Low concentrations of lycorine and cisplatin significantly inhibited the growth and lung metastasis of osteosarcoma cells in vitro and in vivo. • Lycorine combined with cisplatin exerts a synergistic inhibit effect on osteosarcoma cells by suppressing Wnt/β-Catenin and STAT3 signaling pathways. Cisplatin is commonly used in treating osteosarcoma, however, chemoresistance reduces its efficacy and results in a poor prognosis. Lycorine, a Chinese herbal medicine component, possesses anti-tumor and anti-inflammatory properties. This study aims to investigate the combined impact of lycorine and cisplatin on osteosarcoma and its molecular mechanism. The combination of lycorine and cisplatin exhibited a synergistic effect evaluated by MTT and Zheng-Jun Jin's method. Lycorine and cisplatin synergistically inhibit proliferation, migration, invasion, and induce apoptosis of osteosarcoma cells. Pharmacological analysis predicts 13 key targets, including Wnt/β-Catenin and STAT3. After treatment with this combination, key molecules in Wnt/β-Catenin and STAT3 pathways were significantly inhibited. In an orthotopic tumor model, the combination significantly reduces lung metastasis. The present work suggests that a combination of lycorine with cisplatin can effectively inhibit OS cells by suppressing the Wnt/β-Catenin and STAT3 signaling pathways synergistically. This is expected to enhance the therapeutic effect of OS. [ABSTRACT FROM AUTHOR]

• Cocaine-fed larvae developed less in length and weight than the control. • Heroin-fed larvae had a more sluctuating development than the control. • Combination-fed larvae seemed to favour the effects of cocaine rather than heroin. • Cocaine and combination-fed larvae increased second and third instar stages, but shorten pupation and accelerate eclosion. • Heroin increases second instar stage and pupation. Insects present on or near decomposing bodies are collected by forensic entomologists and used to estimate the post-mortem interval. Drugs metabolized by a person before death may affect the rate of development of insects feeding on the corpse. This study aimed to determine the effects of cocaine and heroin main metabolites on the development rate of the Calliphora vomitoria (Diptera: Calliphoridae) and their implications on minimum post-mortem interval determination. Groups of 250 eggs each were placed into four separate pots of 150 g of minced pork meat being either un-spiked, or spiked with benzoylecgonine, morphine, or a combination of both. Larval length (mm) and weight (mg) measurements were taken twice daily and the rate of development of the insects' life cycle was monitored until eclosion. Results show that cocaine-fed larvae developed less in length and weight than the control group. Heroin-fed larvae showed a more fluctuating pattern, being smaller and lighter than the control group for most of their larval cycle, but overtaking them in both parameters towards pupation. Combination-fed larvae seemed to favour the effects of cocaine. The three conditions also had a significant impact on the length of the insects' life cycle. Cocaine and drug combination treatments increased the length of the second and third instar stages, but led to the shortening of pupation and accelerated eclosion. Conversely, heroin treatment led to lengthier pupation. Interestingly, the effects of the drug combination seemed to mirror more precisely those of cocaine. These findings indicate that both cocaine and heroin, singularly and in combination, have sizable effects on blowflies' development rates, potentially biasing post-mortem interval estimations. [ABSTRACT FROM AUTHOR]

The treatment of Alzheimer's disease (AD) is one of the most difficult challenges in neurodegenerative diseases due to the insufficient blood‒brain barrier (BBB) permeability and unsatisfactory intra-brain distribution of drugs. Therefore, we established an ibuprofen and FK506 encapsulated drug co-delivery system (Ibu&FK@RNPs), which can target the receptor of advanced glycation endproducts (RAGE) and response to the high level of reactive oxygen species (ROS) in AD. RAGE is highly and specifically expressed on the lesion neurovascular unit of AD, this property helps to improve targeting specificity of the system and reduce unselective distribution in normal brain. Meanwhile, these two drugs can be specifically released in astrocytes of AD lesion in response to high levels of ROS. As a result, the cognition of AD mice was significantly improved and the quantity of A β plaques was decreased. Neurotoxicity was also alleviated with structural regeneration and functional recovery of neurons. Besides, the neuroinflammation dominated by NF- κ B pathway was significantly inhibited with decreased NF- κ B and IL-1 β in the brain. Overall, Ibu&FK@RNPs can efficiently and successively target diseased BBB and astrocytes in AD lesion. Thus it significantly enhances intracephalic accumulation of drugs and efficiently treats AD by anti-neuroinflammation and neuroprotection. Reactive oxygen species (ROS)-responsive programmed receptor of advanced glycation endproducts (RAGE) targeted delivery depot of Ibu&FK@RNPs was prepared to act on astrocytes and neurons in the treatment of Alzheimer's disease (AD) through anti-neuroinflammation and neuroprotection. [Display omitted] [ABSTRACT FROM AUTHOR]

Esophageal cancer (EC) is one of the most common cancers with high morbidity and mortality rates. EC includes two histological subtypes, namely esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC primarily occurs in East Asia, whereas EAC occurs in Western countries. The currently available treatment strategies for EC include surgery, chemotherapy, radiation therapy, molecular targeted therapy, and combinations thereof. However, the prognosis remains poor, and the overall five-year survival rate is very low. Therefore, achieving the goal of effective treatment remains challenging. In this review, we discuss the latest developments in chemotherapy and molecular targeted therapy for EC, and comprehensively analyze the application prospects and existing problems of immunotherapy. Collectively, this review aims to provide a better understanding of the currently available drugs through in-depth analysis, promote the development of new therapeutic agents, and eventually improve the treatment outcomes of patients with EC. Esophageal cancer (EC) is one of the most common cancers worldwide. This review summarizes the latest developments in chemotherapy, molecular targeted therapy, and immunotherapy for EC. [Display omitted] [ABSTRACT FROM AUTHOR]

Information on Paxlovid™ effectiveness must be monitored and updated in real world scenarios. Our research question was what is the effectiveness of Paxlovid™ in adult patients with COVID-19? Therefore, we investigated the effectiveness of Paxlovid™ on reducing the incidence of pneumonia, hospitalization, and mortality in a cohort of COVID-19 positive adult patients from northeast Mexico. A retrospective cohort study of COVID-19 positive adult patients from Nuevo Leon, Mexico from December 2020 to May 2023 (after Omicron BA-5 circulation) was performed. Paxlovid™ use was authorized in September 2022. Therefore, we analyzed effectiveness in patients with confirmed diagnosis who met selection criteria between September 2022 and May 2023 (n = 20,799; 5,673 with and 15,126 without Paxlovid™). The pneumonia (0.1% vs. 0.4%, p < 0.0001), hospitalization (0.1% vs. 1.2%, p < 0.0001), and death rates (0.04% vs. 0.2%, p < 0.0001) were lower in patients with Paxlovid™ treatment independently of age, sex, comorbidity, and COVID-19 and pneumococcal vaccination history. Effectiveness was 88.2%, 95.9% y 91.9% for pneumonia, hospitalization, and death, respectively. Paxlovid™ reduces the presentation of pneumonia, hospitalization, and death secondary to COVID-19. It is recommended to continue monitoring Paxlovid™ effectiveness, as other SARS-CoV-2 variants continue to emerge. [ABSTRACT FROM AUTHOR]

The possibility to conjugate tumor-targeted cytotoxic nanoparticles and conventional antitumoral drugs in single pharmacological entities would open a wide spectrum of opportunities in nanomedical oncology. This principle has been explored here by using CXCR4-targeted self-assembling protein nanoparticles based on two potent microbial toxins, the exotoxin A from Pseudomonas aeruginosa and the diphtheria toxin from Corynebacterium diphtheriae , to which oligo-floxuridine and monomethyl auristatin E respectively have been chemically coupled. The resulting multifunctional hybrid nanoconjugates, with a hydrodynamic size of around 50 nm, are stable and internalize target cells with a biological impact. Although the chemical conjugation minimizes the cytotoxic activity of the protein partner in the complexes, the concept of drug combination proposed here is fully feasible and highly promising when considering multiple drug treatments aimed to higher effectiveness or when facing the therapy of cancers with acquired resistance to classical drugs. Image, graphical abstract [ABSTRACT FROM AUTHOR]

The synergistic effect of drug combination is one of the most desirable properties for treating cancer. However, systematically predicting effective drug combination is a significant challenge. We report here a novel method based on deep belief network to predict drug synergy from gene expression, pathway and the Ontology Fingerprints-a literature derived ontological profile of genes. Using data sets provided by 2015 DREAM competition, our analysis shows that this integrative method outperforms published results from the DREAM website for 4999 drug pairs, demonstrating the feasibility of predicting drug synergy from literature and the -omics data using advanced artificial intelligence approach. [ABSTRACT FROM AUTHOR]

Limitations of antifungals used in the treatment of candidiasis, as the development of resistant strains, are known by the scientific community. In this context, the aim of this study was to investigate the activity of 2-isopropyl-5-methylphenol (thymol) in combination with fluconazole (FLZ) against clinical Candida strains. The antifungal activity of thymol along with FLZ was evaluated by the Clinical Laboratory Standards Institute (CLSI) M27-A2 broth microdilution method. In addition, synergism was observed for clinical strains of Candida spp. with combination of thymol-FLZ evaluated by the chequerboard microdilution method. The mean of minimum inhibitory concentration (MIC) values of thymol and FLZ were 49.37 and 0.475 μg/ml for C. albicans , 51.25 and 18.80 μg/ml for C. glabrata and 70 and 179.20 μg/ml for C. krusei strains, respectively. Thymol in combination with FLZ exhibited the synergistic effects against all species of Candida tested. FICI values for thymol plus FLZ ranged from 0.366 to 0.607 for C. albicans strains, 0.367 to 0.482 for C. glabrata strains, and 0.375 to 0.563 for C. krusei strains. No antagonistic activity was seen in the strains tested. Thymol was found to have a fungicidal effect on Candida species and a synergistic effect when combined with FLZ. [ABSTRACT FROM AUTHOR]

Objective: Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. Methods: Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative reverse transcriptase-polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets. Results: Ovarian cancer cell lines and the patients' ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1 and CDC25B, leading to cell death in both cell lines and patients' ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients' ascites cells ex vivo. Conclusion: Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Objective: Aberrantly activated FOXM1 (forkhead box proteinM1) leading to uncontrolled cell proliferation and dysregulation of FOXM1transcription network occurs in 84%of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. Methods: Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative real-time polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets. Results: Ovarian cancer cell lines and the patients' ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1, CDC25B, leading to cell death in both cell lines and patients' ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients' ascites cells ex vivo. Conclusion: Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis complex, still presents significant numbers of incidence and mortality, in addition to several cases of drug resistance. Resistance, especially to isoniazid, which is one of the main drugs used in the treatment, has increased. In this context, N -acylhydrazones derived from isoniazid have shown important anti- Mycobacterium tuberculosis activity. Hence, this work aimed to determine the anti-TB potential of 11 isoniazid- N -acylhydrazones (INH-acylhydrazones). For this purpose, the determination of minimum inhibitory concentration (MIC) against M. tuberculosis H 37 Rv and clinical isolates was carried out. Drug combination, minimum bactericidal concentration, cytotoxicity, and in silico parameters were also performed. INH-acylhydrazones (2), (8), and (9) had MIC for M. tuberculosis H 37 Rv similar to or lower than isoniazid, and bactericidal activity was observed. In addition, these compounds showed low cytotoxicity, with a selectivity index greater than 3,000. Interesting results were also obtained in the drug combination assay, with synergistic combinations with isoniazid, ethambutol, and rifampicin. In the in silico study, INH-acylhydrazones behaved similarly to INH, but with improvements in some aspects. Based on these findings, it is concluded that compounds (2), (8), and (9) are considered promising scaffolds and warrant further investigation for designing future antimicrobial drugs. [ABSTRACT FROM AUTHOR]

• Multicomponent therapeutic strategies or fixed-dose combinations (FDC) are the latest approach in drug design for the treatment of complex diseases. • This study demonstrated the potential anti-lung cancer activities of a combination of cucurbitacin E (CuE) and myricetin (Myr) from Citrullus colocynthis (L.) Schrad. • The combination drug is based on an advanced understanding of the roles of autophagy and the PI3K/AKT/mTOR signaling pathway in lung cancer treatment, based on the network pharmacology and molecular docking approach. Non-small cell lung cancer (NSCLC) is associated with extremely high morbidity and mortality rates worldwide. Citrullus colocynthis (L.) Schrad, widely distributed in Asian and African countries, is used to treat cancers in traditional Uyghur medicine. The combination of Cucurbitacin E (CuE) and Myricetin (Myr) of C. colocynthis could treat NSCLC by targeting autophagy. The potential anti-cancer components (CuE and Myr) of C. colocynthis were identified using in-silico methods and further in vitro explored the anti-NSCLC properties of the combination of CuE and Myr. Network pharmacology and molecular docking were used to identify potential therapeutic compounds of C. colocynthis for the treatment of NSCLC. In A549 cells, the anti-cancer activities and synergy of CuE and Myr were studied using CompuSyn, their mechanism behind autophagy regulation was determined by western blotting and immunofluorescence staining. CuMy-12 (CuE: 0.5 µM, Myr: 20 µM), a combination of CuE and Myr from C. colocynthis , inhibited A549 cell proliferation and colony formation, and induced apoptosis and cell cycle arrest in the G0/G1 phase, exhibiting a synergistic effect. Furthermore, CuMy-12 inhibited autophagy and activation of the PI3K/AKT/mTOR signaling pathway, which was characterized by a decrease in Beclin 1, AKT, and phospho-AKT proteins. CuMy-12 can be considered a natural candidate with anticancer activity for autophagy-based regulation, but mechanistic and clinical studies are required to validate its potential. [Display omitted] [ABSTRACT FROM AUTHOR]

• Fam20C inhibitor (3R) is in combination with paclitaxel for potential triple-negative breast cancer therapy. • The combination of Fam20C inhibitor (3R) and paclitaxel can induce TNBC cell apoptosis. • Fam20C inhibitor (3R) downregulates the expression of LIF and cyclin D1 in BT-549 cells. • Fam20C inhibitor (3R) and paclitaxel can regulate LIF-JAK2/STAT3 pathway in TNBC. Triple negative breast cancer (TNBC) is a strongly proliferative, relapse prone, high-mortality subtype of breast cancer. Due to the lack of effective therapeutic targets, the current clinical treatment is still dominated by chemotherapeutic drugs, such as paclitaxel (PTX). Moreover, Fam20C kinase inhibitor (3R) has recently been reported to inhibit TNBC growth. Thus, the objectives of this study were to verify whether the combination therapy with 3R could enhance the efficacy of PTX treatment on TNBC, and to further elucidate their potential synergistic mechanisms. The inhibitory effect on TNBC cell viability was verified by the MTT assay, and the effect of drug combination on apoptosis was analyzed by flow cytometry. The mechanism of action of the drug combination was validated based on transcriptome analyses and western blot (WB) analysis. Xenograft mouse models were used to verify the therapeutic efficacy of PTX+3R in vivo by immunohistochemistry and WB analysis. Fam20C inhibitor (3R) enhanced the inhibitory effect of PTX on the viability and proliferation of MDA-MB-231 and BT-549 cells, and their combination significantly promoted cell apoptosis. In addition, we found that 3R reduced the expression of leukemia inhibitor factor (LIF). 3R and PTX limit the phosphorylation activation of signal transducer and activator of translation 3 (STAT3). Finally, immunohistochemical staining showed that combined treatment with 3R and PTX inhibited tumor growth in an ectopic tumor model of MDA-MB-231 cells in nude mice. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Danhong injection (DHI) is quite often used in combination with low-dose aspirin (ASA, 75-325mg daily) in clinic, particularly for the treatment of cardiovascular diseases. Exploring their interaction profile is of great clinical importance.Purpose: The current study aims to explore the interaction between DHI and low-dose ASA in rats.Methods: Sixty four rats were randomly divided into eight groups. Stomach and other four vital organs were collected for histological evaluation. Organs which exhibited histological changes were selected for a further study to evaluate the damage score and mode of action. We tested the protective effect of DHI on gastric mucosal damage in different regimes of administration. COX activity, gastric mucus secretion, pepsin activity, antioxidant activity and ROS level were assayed to reflect the protective effect of DHI on gastric mucosal damage induced by ASA.Results: Stomach was the target organ of interaction when DHI and ASA were used in combination. DHI alleviated gastric mucosal damage by 55.8% when DHI was injected before ASA (Group E) and by 53.5% when DHI was injected 2h after ASA administration (Group F). Additionally, if DHI treatment was appended to the long-term administration of ASA, DHI still decreased the gastric mucosal damage score in 52.0% from 2.50 to 1.20. DHI improved gastric mucus secretion, as well as decreased pepsin activity to maintain the integrity of gastric mucosal barrier (P<0.05). Furthermore, DHI recovered antioxidant activity which was impaired by ASA. In details, DHI decreased gastric mucosal ROS level, increased CAT, GSH-Px and SOD activity, and reduced MDA concentration (P<0.05). When ASA (71.9µM) was used in combination with DHI (23-fold dilution, presented in terms of concentrations of DSS, PA, SaD RA, SaB and SaA were 6.45-6.92, 1.10-1.14, 1.09-1.10, 0.86-0.90, 16.76-19.38 and 1.83-1.94µg/ml, respectively) in vitro, the inhibition rate of ASA increased from 38.6% (ASA alone) to 62.8% (ASA-DHI) on COX-1 and from 28.9% (ASA alone) to 38.8% (ASA-DHI) on COX-2 (P<0.05). DHI strengthened the inhibition activity of ASA on both COX-1 and COX-2, which showed that DHI alleviated ASA induced gastric mucosal damage but not antagonized anti-COX effect of ASA.Conclusions: Gastric protective benefits were clearly produced when DHI and ASA were used in combination, which provided rational guidance for clinical combined application of DHI and ASA. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cordycepin combined with doxorubicin could significantly inhibit the activity, proliferation and migration of HepG-2 cells. • The combination of the two drugs can significantly inhibit the proliferation of transplanted HepG-2 in nude mice. • Based on the study of molecular mechanism of anti HCC by combination of drugs, MYC may be a potential target in the treatment of HCC. • Combination therapy for hepatocellular Carcinoma (HCC) is a multi-target and multi-pathway mechanism. Liver cancer is a serious disease with global impact. Due to the poor prognosis of liver cancer, there is an urgent need to develop new therapeutic options. The aim of the present study was to investigate the feasibility of cordycepin combined with doxorubicin for the treatment of liver cancer and its mechanism of action. In vitro and in vivo studies revealed that cordycepin combined with doxorubicin effectively inhibited cell proliferation and induced apoptosis in hepatocellular carcinoma. Network pharmacology analysis of the anticancer mechanism of cordycepin combined with doxorubicin showed that 82 potential targets were enriched in "Proteoglycans in cancer", "TNF signaling pathway", "MicroRNAs in cancer", "Epithelial cell signaling in Helicobacter pylori infection", "Pathways in cancer". MYC is the target with the largest Degree value in the PPI network, revealing that MYC may play an important role in combination anticancer. It was further suggested that combined treatment could downstream of c-Myc to regulate apoptosis-related genes, such as BCL2 , MCL1 , PARP1 and CASP3 , thereby inducing apoptosis. At the same time, we demonstrated that the drug combination regulated the expression of genes related to cell migration, such as MMP9 , MMP3 and ICAM1 , thereby inhibiting cell migration. In vivo , the combined treatment suppressed the growth of HepG-2 xenograft-bearing nude mice by inducing apoptosis, and the inhibition rate of the combination group was higher than that of the single treatment group. In summary, the present study demonstrated that cordycepin potentiates the sensitivity of liver cancer cells to doxorubicin, suggesting that it may be a potential anticancer drug. [ABSTRACT FROM AUTHOR]

Background: The current treatment of Chagas disease, endemic in Latin America and emerging in several countries, is limited by the frequent side effects and variable efficacy of benznidazole. Natural products are an important source for the search for new drugs.Aim/hypothesis: Considering the great potential of natural products as antiparasitic agents, we investigated the anti-Trypanosoma cruzi activity of a concentrated ethanolic extract of Physalis angulata (EEPA).Methods: Cytotoxicity to mammalian cells was determined using mouse peritoneal macrophages. The antiparasitic activity was evaluated against axenic epimastigote and bloodstream trypomastigote forms of T. cruzi, and against amastigote forms using T. cruzi-infected macrophages. Cell death mechanism was determined in trypomastigotes by flow cytometry analysis after annexin V and propidium iodide staining. The efficacy of EEPA was examined in vivo in an acute model of infection by monitoring blood parasitaemia and survival rate 30 days after treatment. The effect against trypomastigotes of EEPA and benznidazole acting in combination was evaluated.Results: EEPA effectively inhibits the epimastigote growth (IC50 2.9 ± 0.1 µM) and reduces bloodstream trypomastigote viability (EC50 1.7 ± 0.5 µM). It causes parasite cell death by necrosis. EEPA impairs parasite infectivity as well as amastigote development in concentrations noncytotoxic to mammalian cells. In mice acutely-infected with T. cruzi, EEPA reduced the blood parasitaemia in 72.7%. When combined with benznidazole, EEPA showed a synergistic anti-T. cruzi activity, displaying CI values of 0.8 ± 0.07 at EC50 and 0.83 ± 0.1 at EC90.Conclusion: EEPA has antiparasitic activity against T. cruzi, causing cell death by necrosis and showing synergistic activity with benznidazole. These findings were reinforced by the observed efficacy of EEPA in reducing parasite load in T. cruzi-mice. Therefore, this represents an important source of antiparasitic natural products. [ABSTRACT FROM AUTHOR]

Resistance to cytarabine and anthracycline-based chemotherapy is a major cause of treatment failure for acute myeloid leukemia (AML) patients. Overexpression of Bcl-2, Bcl-xL, and/or Mcl-1 has been associated with chemoresistance in AML cell lines and with poor clinical outcome of AML patients. Thus, inhibitors of anti-apoptotic Bcl-2 family proteins could be novel therapeutic agents. In this study, we investigated how clinically achievable concentrations of obatoclax, a pan-Bcl-2 inhibitor, potentiate the antileukemic activity of cytarabine in AML cells. MTT assays in AML cell lines and diagnostic blasts, as well as flow cytometry analyses in AML cell lines revealed synergistic antileukemic activity between cytarabine and obatoclax. Bax activation was detected in the combined, but not the individual, drug treatments. This was accompanied by significantly increased loss of mitochondrial membrane potential. Most importantly, in AML cells treated with the combination, enhanced early induction of DNA double-strand breaks (DSBs) preceded a decrease of Mcl-1 levels, nuclear translocation of Bcl-2, Bcl-xL, and Mcl-1, and apoptosis. These results indicate that obatoclax enhances cytarabine-induced apoptosis by enhancing DNA DSBs. This novel mechanism provides compelling evidence for the clinical use of BH3 mimetics in combination with DNA-damaging agents in AML and possibly a broader range of malignancies. [ABSTRACT FROM AUTHOR]

Background: Psoraleae Fructus has been widely used in China and its surroundings; however, Psoraleae Fructus and its compound preparation have been reported recently to cause liver injury in clinics. Thus, its safe use has attracted increasing attention. The possible mechanism is related to the metabolism of psoralen, but it still needs further clarification.Purpose: The present study was designed to evaluate the toxicity of psoralen and investigate the potentially related molecular mechanisms using chemical biology methods combined with animal experiments to provide evidence for the rational clinical use of psoralen.Methods: An in vivo experiment was conducted with a time series of 20-80 mg/kg psoralen to verify its toxic performance. Target capture and click reactions were used to investigate direct targets of psoralen. Selectivity for different glutathione-S-transferase (GST) subtypes in the liver and inhibition of cytochrome P450 (CYP450) were also detected.Results: Psoralen build-up in the liver is the primary cause of liver damage. Our study revealed the mechanism by which psoralen induces liver injury. Psoralen can bind directly to CYP2D6, CYP3A4, GST-α, and GST-μ and inhibit their activities, causing the depletion of glutathione (GSH) in vivo, which in turn induces hepatic damage. The special structure of α,β-unsaturated lactones in psoralen facilitates its attachment to its target; therefore, complementing psoralen with GSH can efficiently protect the liver from damage.Conclusions: Psoralen causes a disorder in drug metabolism by inhibiting the activity of CYPs and GSTs, causing exhaustion of GSH, and subsequently leading to liver damage. The co-administration of GSH and psoralen is an effective way to avoid liver injury in clinical settings. [ABSTRACT FROM AUTHOR]

Copyright of Arquivos Brasileiros de Oftalmologia is the property of Arquivos Brasileiros de Oftalmologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background & Aims: The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated because of their side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined the safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection. Methods: We analyzed data from 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were assigned randomly to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary end point was an HCV-RNA level less than 25 IU/mL at 12 weeks after treatment (sustained virologic response at 12 weeks [SVR12]). Results: In 64 patients, HCV-RNA levels were less than 25 IU/mL by week 4 of treatment (including 48 of 49 patients with HCV genotype 1a infection and 45 of 46 patients with the non-CC interleukin 28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3–4 increases in levels of alanine or aspartate aminotransferases or bilirubin; there were no deaths or discontinuations resulting from serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms. Conclusions: In a phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted. ClinicalTrials.gov, number NCT01455090. [Copyright &y& Elsevier]

Selenium is an essential trace element that is crucial for cellular antioxidant defense against reactive oxygen species (ROS). Recently, many selenium-containing compounds have exhibited a wide spectrum of biological activities that make them promising scaffolds in Medicinal Chemistry, and, in particular, in the search for novel compounds with anticancer activity. Similarly, certain tellurium-containing compounds have also exhibited substantial biological activities. Here we provide an overview of the biological activities of seleno- and tellurocompounds including chemopreventive activity, antioxidant or pro-oxidant activity, modulation of the inflammatory processes, induction of apoptosis, modulation of autophagy, inhibition of multidrug efflux pumps such as P-gp, inhibition of cancer metastasis, selective targeting of tumors and enhancement of the cytotoxic activity of chemotherapeutic drugs, as well as overcoming tumor drug resistance. A review of the chemistry of the most relevant seleno- or tellurocompounds with activity against resistant cancers is also presented, paying attention to the synthesis of these compounds and to the preparation of bioactive selenium or tellurium nanoparticles. Based on these data, the use of these seleno- and tellurocompounds is a promising approach in the development of strategies that can drive forward the search for novel therapies or adjuvants of current therapies against drug-resistant cancers. [ABSTRACT FROM AUTHOR]

Abstract: Soil-transmitted helminths cause more than 1billion human infections globally, mostly in the poorest regions of the world. Control relies essentially on a limited panel of four drugs, and drug resistance might be inescapable. Nitazoxanide, an anti-infective drug, has been shown to exert anthelmintic activity in human clinical trials. In the present work, nitazoxanide was tested alone or combined with commercialized anthelmintics on Trichuris muris, a whipworm mouse model, and Ancylostoma ceylanicum, a hookworm hamster model, in vitro and in vivo. IC50s of ⩽1 and 12.87μg/ml were achieved with nitazoxanide on T. muris third-stage larvae (L3) and adult worms in vitro, respectively. An IC50 of ⩽1μg/ml was obtained exposing A. ceylanicum adults worms to nitazoxanide, whereas A. ceylanicum L3 were not affected. Using scanning electron microscopy, the tegument of adult T. muris appeared unchanged following nitazoxanide treatment, whereas swellings were seen on the tegument of the anterior region of half of the A. ceylanicum specimen analyzed. Synergism was observed in vitro when nitazoxanide was combined with levamisole or ivermectin on T. muris adult worms, and when combined with levamisole, pyrantel pamoate, or ivermectin on A. ceylanicum adult worms. In T. muris-infected mice, oral nitazoxanide achieved worm burden reductions of 56.09% and 17.37% following a single dose of 100mg/kg and three doses of 50mg/kg, respectively. None of the tested drug combinations displayed activity on T. muris in vivo. In A. ceylanicum-infected hamsters, no effect was observed for oral nitazoxanide alone, and none of the tested combinations reached the threshold for additive effect. In conclusion, nitazoxanide failed to demonstrate promising activity against T. muris and A. ceylanicum in vivo, regardless whether tested as monotherapy or combined with standard drugs. Reasons for the discrepancy of these findings compared to results obtained in clinical trials remain to be elucidated. [Copyright &y& Elsevier]

Abstract: When the pathophysiology of a medical condition is multimodal, ie, related to multiple physiological causes or mediated by multiple pathways, the optimal strategy can be to use a drug or a combination of drugs that contribute multiple mechanisms to the therapeutic endpoint. In such situations, a rational multimodal approach can also result in the fewest adverse effects. We discuss the quantitative analysis of multimodal action using the treatment of pain as a practical example and give examples of its application to some widely used analgesic drugs. Perspective: This article reviews the medical relevance of the quantitative evaluation of drug combinations, using pain and combinations of analgesics as specific examples. Such measure can help clinicians who seek to maximize therapeutic effect while simultaneously minimizing adverse effects. [ABSTRACT FROM AUTHOR]

The article discusses research on the safety and efficacy of fixed-dose combinations (FDC) of antihypertensive agents. It references a study by Ajay K. Gupta and colleagues, published in the 2010 issue of "Hypertension." The researchers performed a meta-analysis to assess the blood pressure (BP) control with FDC in comparison with their free-drug components. They also mention that it is not clear if FDC of two antihypertensive agents in a single tablet offers greater benefits than the agents.

Abstract: Cancer cells contain multiple signal transduction pathways whose activities are frequently elevated due to their transformation, and that are often activated following exposure to established cytotoxic therapies including ionizing radiation and chemical DNA damaging agents. Many pathways activated in response to transformation or toxic stresses promote cell growth and invasion and counteract the processes of cell death. As a result of these findings many drugs, predominantly protein and lipid kinase inhibitors, of varying specificities, have been developed to block signaling by cell survival pathways in the hope of killing tumor cells and sensitizing them to toxic therapies. Unfortunately, due to the plasticity of signaling processes within a tumor cell, inhibition of any one growth factor receptor or signaling pathway frequently has only modest long-term effects on cancer cell viability, tumor growth, and patient survival. As a result of this realization, a greater emphasis has begun to be placed on rational combinations of drugs that simultaneously inhibit multiple inter-linked signal transduction/survival pathways. This, it is hoped, will limit the ability of tumor cells to adapt and survive because the activity within multiple parallel survival signaling pathways has been reduced. This review will discuss some of the approaches that have been taken to combine signal transduction modulatory agents to achieve enhanced tumor cell killing. [Copyright &y& Elsevier]

Copyright of Drug Research / Arzneimittel-Forschung (Editio Cantor Verlag fur Medizin und Naturwissenschaften) is the property of Editio Cantor Verlag fur Medizin und Naturwissenschaften and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

As multi-drug preparations have come past the era of intuitive composition, their value is increasingly recognized. Improved treatment compliance is an accepted advantage, in particular in diseases without overt distress such as earlier-stage diabetes mellitus, type 2, but does not suffice for market authorization. For preparations composed of more than one active substance, the prevailing guidelines rule that each constituent must contribute to efficacy (or improve tolerability); effective and safe doses must be used and pharmacokinetic interactions between the active ingredients must be excluded or clearly defined. In the typical case, the combination must demonstrate enhanced efficacy, with a largely unchanged risk profile, or improvement of tolerability at constant efficiency. These requirements are convincingly met with a recently registered drug, Avandament®, which is metformin MCI (CAS 1115-70-4) and a thiazolidinedione, rosiglitazone maleate (CAS 155141-29-0), in one tablet. By complementary actions, the two components cover both hepatic and peripheral sites of action to restitute insulin sensitivity. Acting on a variety of targets, rosiglitazone is able to overcome insulin resistance in patients with insufficient response to maximally dosed metformin. For example, adding rosiglita zone (8 mg/day) to an ongoing treatment with metformin (2.5 g/day) resulted in a drop of glycosylated hemoglobin by 1.2%. Pharmacokinetics of the two constituents fall into the same range and are not altered by coadministration (range 3.4-4.3 h). As the tolerability profiles of the two drugs show little overlap, the drug combination is well tolerated; the risk of hypoglycemia is low (less than 3 %) and precautions and contraindications are largely those of the active ingredients. In sum, the combination of metformin and rosiglitazone in a single tablet displays an improved benefit/risk ratio with regard to its constituents. [ABSTRACT FROM AUTHOR]