Synergistic Effect Of Combination Research Articles

Synergistic bactericidal mechanisms of RF energy simultaneously combined with cinnamon essential oil or epsilon-polylysine against Salmonella revealed at cellular and metabolic levels

Radio frequency (RF) heating and antimicrobials are considered to be effective methods for inactivating food pathogens. This study explored the bactericidal effects against Salmonella of RF heating combined with two kinds of natural antimicrobials possessing different hydrophobic properties and their synergistic bactericidal mechanisms. Results showed that RF heating caused sublethal damage to bacterial cells and enhanced the interaction of cells and antimicrobials, leading to synergistic bactericidal effects of the simultaneous combination of RF heating and antimicrobials. The combination of RF heating and ε-polylysine (ε-PL) further promoted cell morphological alteration, raised membrane permeability, intracellular adenosine triphosphate (ATP) leakage and intracellular reactive oxygen species (ROS) accumulation compared to individual treatment. The simultaneous combination of RF heating and cinnamon essential oil nanoemulsion (CEON) also further enhanced membrane permeability and ROS accumulation compared to individual treatment, but impacts were less than those in the combination of RF heating and ε-PL. The major synergistic bactericidal mechanism of RF heating and CEON was significantly inhibiting intracellular ATP synthesis. The untargeted metabolomics analysis revealed that the combined treatments enhanced disturbances to multiple intracellular metabolisms compared to individual treatment, thus leading to synergistic bactericidal effects against Salmonella. These results provide an in-depth understanding of the synergistic bactericidal mechanisms of the combination of RF heating and natural antimicrobials from cellular and metabolic levels.

Characterization and Bio-Evaluation of the Synergistic Effect of Simvastatin and Folic Acid as Wound Dressings on the Healing Process.

Wound healing is a significant healthcare problem that decreases the patient's quality of life. Hence, several agents and approaches have been widely used to help accelerate wound healing. The challenge is to search for a topical delivery system that could supply long-acting effects, accurate doses, and rapid healing activity. Topical forms of simvastatin (SMV) are beneficial in wound care. This study aimed to develop a novel topical chitosan-based platform of SMV with folic acid (FA) for wound healing. Moreover, the synergistic effect of combinations was determined in an excisional wound model in rats. The prepared SMV-FA-loaded films (SMV-FAPFs) were examined for their physicochemical characterizations and morphology. Box-Behnken Design and response surface methodology were used to evaluate the tensile strength and release characteristics of the prepared SMV-FAPFs. Additionally, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction pattern (XRD), and animal studies were also investigated. The developed SMV-FAPFs showed a contraction of up to 80% decrease in the wound size after ten days. The results of the quantitative real-time polymerase chain reaction (RT-PCR) analysis demonstrated a significant upregulation of dermal collagen type I (CoTI) expression and downregulation of the inflammatory JAK3 expression in wounds treated with SMV-FAPFs when compared to control samples and individual drug treatments. In summary, it can be concluded that the utilization of SMV-FAPFs holds great potential for facilitating efficient and expeditious wound healing, hence presenting a feasible substitute for conventional topical administration methods.

Dinaciclib synergizes with BH3 mimetics targeting BCL-2 and BCL-XL in multiple myeloma cell lines partially dependent on MCL-1 and in plasma cells from patients.

A better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological strategies are needed. Dinaciclib, a multiple cyclin-dependent kinase (CDK) inhibitor, which inhibits CDK1, 2, 5 and 9, displays significant antimyeloma activity as found in phase II clinical trials. In this study, we have explored the mechanism of dinaciclib-induced death and evaluated its enhancement by different BH3 mimetics in MM cell lines as well as in plasma cells from MM patients. Our results indicate a synergistic effect of dinaciclib-based combinations with B-cell lymphoma 2 or B-cell lymphoma extra-large inhibitors, especially in MM cell lines with partial dependence on myeloid cell leukemia sequence 1 (MCL-1). Simultaneous treatment with dinaciclib and BH3 mimetics ABT-199 or A-1155463 additionally showed a synergistic effect in plasma cells from MM patients, ex vivo. Altered MM cytogenetics did not affect dinaciclib response ex vivo, alone or in combined treatment, suggesting that these combinations could be a suitable therapeutic option for patients bearing cytogenetic alterations and poor prognosis. This work also opens the possibility to explore cyclin-dependent kinase 9 inhibition as a targeted therapy in MM patients overexpressing or with high dependence on MCL-1.

Diethylcarbamazine elicits Ca2+ signals through TRP-2 channels that are potentiated by emodepside in Brugia malayi muscles.

Filarial nematode infections are a major health concern in several countries. Lymphatic filariasis is caused by Wuchereria bancrofti and Brugia spp. affecting over 120 million people. Heavy infections can lead to elephantiasis, which has serious effects on individuals' lives. Although current anthelmintics are effective at killing microfilariae in the bloodstream, they have little to no effect against adult parasites found in the lymphatic system. The anthelmintic diethylcarbamazine is one of the central pillars of lymphatic filariasis control. Recent studies have reported that diethylcarbamazine can open transient receptor potential (TRP) channels in the muscles of adult female Brugia malayi, leading to contraction and paralysis. Diethylcarbamazine has synergistic effects in combination with emodepside on Brugia, inhibiting motility: emodepside is an anthelmintic that has effects on filarial nematodes and is under trial for the treatment of river blindness. Here, we have studied the effects of diethylcarbamazine on single Brugia muscle cells by measuring the change in Ca2+ fluorescence in the muscle using Ca2+-imaging techniques. Diethylcarbamazine interacts with the transient receptor potential channel, C classification (TRPC) ortholog receptor TRP-2 to promote Ca2+ entry into the Brugia muscle cells, which can activate Slopoke (SLO-1) Ca2+-activated K+ channels, the putative target of emodepside. A combination of diethylcarbamazine and emodepside leads to a bigger Ca2+ signal than when either compound is applied alone. Our study shows that diethylcarbamazine targets TRP channels to promote Ca2+ entry that is increased by emodepside activation of SLO-1 K+ channels.

Inhalable Combination Powder Formulations for Treating Latent and Multidrug-Resistant Tuberculosis: Formulation and In Vitro Characterization.

Tuberculosis (TB) is an infectious disease resulting in millions of deaths annually worldwide. TB treatment is challenging due to a huge number of global latent infections and due to multidrug-resistant forms of TB. Inhaled administration of anti-TB drugs using dry powder inhalers has various advantages over oral administration due to its direct drug delivery and minimization of systemic side effects. Pretomanid (PA-824, PA) is a relatively new drug with potent activity against both active and latent forms of Mycobacterium tuberculosis (Mtb). It is also known for its synergistic effects in combination with pyrazinamide (PYR) and moxifloxacin (MOX). Fixed-dose combination powder formulations of either PYR and PA or PYR and MOX were prepared for inhaled delivery to the deep lung regions where the Mtb habitats were located. Powder formulations were prepared by spray drying using L-leucine as the aerosolization enhancer and were characterized by their particle size, morphology and solid-state properties. In vitro aerosolization behaviour was studied using a Next Generation Impactor, and stability was assessed after storage at room temperature and 30% relative humidity for three months. Spray drying with L-leucine resulted in spherical dimpled particles, 1.9 and 2.4 µm in size for PYR-PA and PYR-MOX combinations, respectively. The powder formulations had an emitted dose of >83% and a fine particle fraction of >65%. PA and MOX showed better stability in the combination powders compared to PYR. Combination powder formulations with high aerosolization efficiency for direct delivery to the lungs were developed in this study for use in the treatment of latent and multidrug-resistant TB infections.

Electrochemical determination of Vitamin B6 using coral-like MnO2-Pi on Ti3C2Tx MXene

MXenes are 2D nanomaterials that are considered the materials of the future generation due to their high electrical conductivity, good biocompatibility, and ease of functionalization. This research work reports the electrochemical sensing of Vitamin B6 using the Manganese dioxide-inorganic phosphate/MXene brush-coated Carbon fiber paper electrode (MnO2-Pi/MXene/CFP) electrode for the first time. The three-dimensional Ti3C2Tx MXene nanosheets consisting of highly ordered, vertically aligned nanosheets with electrochemically deposited MnO2-Pi are capable of yielding a synergistic effect in combination with high electrochemical performance and large surface area of MnO2-Pi. The reported electrochemical sensor exhibited a wide linear dynamic range (0.06–650 µM) and a low-level detection limit of 0.021 µM. An increase in the anodic peak current confirms the rapid transfer of electrons transfer arising between the Ti3C2Tx MXene and MnO2-Pi. The results attained substantiate that the fabricated sensor has enhanced selectivity, reproducibility, and stability toward the electrochemical determination of Vitamin B6 in real samples.

Efficient synergistic combination effect of curcumin with piperine by polymeric magnetic nanoparticles for breast cancer treatment

Although it has been reported that the co-delivery of drugs can be beneficial to patients to kill breast cancer cells, the delivery methods could only be employed to effectively encapsulate individual curcumin (CUR) or piperine (PIP) molecules due to their different molecular polarities. Therefore, in the current research, an attempt was made to overcome the limitation of the co-delivery of CUR and PIP nanoparticles for breast cancer therapy. To manage locoregional breast cancer recurrence, a magnetic co-delivery system of CUR and PIP against MCF-7 breast cancer cells was examined. CUR and PIP demonstrated synergistic effects for breast cancer therapy when utilized together. However, due to the different polarities of CUR and PIP, it was difficult to co-encapsulate them in conventional delivery systems. Moreover, their low bioavailability, hydrophobic nature, and low cellular uptake limit its usage for cancer therapy. In the current study, to overcome the issues and improves its therapeutic efficacy, CUR and PIP-loaded zein/chitosan-coated iron oxide (Chit-PIP/[email protected]3O4) were prepared via a combination of anti-solvent precipitation and layer-by-layer deposition. X-ray diffraction (XRD) analysis revealed magnetite cores and also showed that the binding process did not change the Fe3O4 phase. A vibrational sample magnetometer confirmed that the saturation of sample magnetization was 60 and 40 emu/g for pure Fe3O4 and nanocomposite, respectively. Nanoparticles with an average size of 20 nm were prepared. The drug-loading content of CUR and PIP was approximately 18% and 16%, respectively. CUR and PIP release from Chit-PIP/[email protected]3O4 was faster at the extracellular pH of around tumors (6.5) than in normal tissues (7.4), an interesting degree of pH sensitivity. The MTT assay exhibited that PIP/CUR-loaded polymeric magnetic nanoparticles had significant synergistic cytotoxicity against MCF-7 cells compared with other groups. These results demonstrate that the combination of dual-drug loaded polymeric magnetic nanoparticles holds promise for the targeted treatment of cancer cells.

Dual-targeting peptides@PMO, a mimetic to the pro-apoptotic protein Smac/DIABLO for selective activation of apoptosis in cancer cells.

The refractoriness of tumor cells to apoptosis represents the main mechanism of resistance to chemotherapy. Smac/DIABLO mimetics proved to be effective in overcoming cancer-acquired resistance to apoptosis as a consequence of overexpression of the anti-apoptotic proteins XIAP, cIAP1, and cIAP2. In this work, we describe a dual-targeting peptide capable of selectively activating apoptosis in cancer cells. The complex consists of a fluorescent periodic mesoporous organosilica nanoparticle that carries the short sequences of Smac/DIABLO bound to the αvβ3-integrin ligand. The dual-targeting peptide @PMO shows significantly higher toxicity in αvβ3-positive HeLa cells with respect to αvβ3-negative Ht29 cells. @PMO exhibited synergistic effects in combination with oxaliplatin in a panel of αvβ3-positive cancer cells, while its toxicity is overcome by XIAP overexpression or integrin β3 silencing. The successful uptake of the molecule by αvβ3-positive cells makes @PMO promising for the re-sensitization to apoptosis of many cancer types.

The co-presence of polystyrene nanoplastics and ofloxacin demonstrates combined effects on the structure, assembly, and metabolic activities of marine microbial community

Nanoplastic is increasing in environments and can address toxic effects on various organisms. Particle size, concentration, and surface functionalization most influence nanoplastic toxicity. Besides, nanoplastic can adsorb other contaminants (e.g., antibiotics) to aggravate its adverse effects. The combined effects of nanoplastics and antibiotics on planktonic/benthic microbial communities, however, are still largely unknown. In this study, the combined effects of polystyrene nanoplastic and ofloxacin on the structure, assembly, and metabolic activities of marine microbial communities were investigated based on amplicon sequencing data. The results mainly demonstrate that: (1) nanoplastic and ofloxacin have greater impacts on prokaryotic communities than eukaryotic ones; (2) niche breadths of planktonic prokaryotes and benthic eukaryotes were shrank with both high nanoplastic and ofloxacin concentrations; (3) increased ofloxacin mainly reduces nodes/edges of co-occurrence networks, while nanoplastic centralizes network modularity; (4) increased nanoplastic under high ofloxacin concentration induces more differential prokaryotic pathways in planktonic communities, while benthic communities are less influenced. The present work indicates that co-presence of nanoplastics and ofloxacin has synergistic combined effects on community structure shifts, niche breadth shrinking, network simplifying, and differential prokaryotic pathways inducing in marine microbial communities, suggesting nanoplastics and its combined impacts with other pollutions should be paid with more concerns.

A disintegrin and metalloproteinase 22 activates integrin β1 through its disintegrin domain to promote the progression of pituitary adenoma.

Approximately 35% of pituitary adenoma (PA) display an aggressive profile, resulting in low surgical total resection rates, high recurrence rates, and worse prognosis. However, the molecular mechanism of PA invasion remains poorly understood. Although "a disintegrin and metalloproteinases" (ADAMs) are associated with the progression of many tumors, there are no reports on ADAM22 in PA. PA transcriptomics databases and clinical specimens were used to analyze the expression of ADAM22. PA cell lines overexpressing wild-type ADAM22, the point mutation ADAM22, the mutated ADAM22 without disintegrin domain, and knocking down ADAM22 were generated. Cell proliferation/invasion assays, flow cytometry, immunohistochemistry, immunofluorescence, co-immunoprecipitation, mass spectrometry, Reverse transcription-quantitative real-time PCR, phos-tag SDS-PAGE, and Western blot were performed for function and mechanism research. Nude mice xenograft models and rat prolactinoma orthotopic models were used to validate in vitro findings. ADAM22 was significantly overexpressed in PA and could promote the proliferation, migration, and invasion of PA cells. ADAM22 interacted with integrin β1 (ITGB1) and activated FAK/PI3K and FAK/ERK signaling pathways through its disintegrin domain to promote PA progression. ADAM22 was phosphorylated by PKA and recruited 14-3-3, thereby delaying its degradation. ITGB1-targeted inhibitor (anti-itgb1) exerted antitumor effects and synergistic effects in combination with somatostatin analogs or dopamine agonists in treating PA. ADAM22 was upregulated in PA and was able to promote PA proliferation, migration, and invasion by activating ITGB1 signaling. PKA may regulate the degradation of ADAM22 through post-transcriptional modification levels. ITGB1 may be a potential therapeutic target for PA.

ROS-Responsive Prodrug Micelle Co-Delivery System for Synergistic Antiatherosclerotic Therapy.

Tanshinone IIA (TS-IIA) and salvianic acid A (SAA) are the main pharmacological active constituents of Danshen, which exhibit potent effects on atherosclerosis. A combination of TS-IIA and SAA might exert a synergistic antiatherosclerotic effect. However, the opposite solubility profiles of TS-IIA and SAA might lead to difficulty in achieving a synergistic combined effect of the two active components. Therefore, in this work, we fabricated a ROS-responsive prodrug micelle for the codelivery of TS-IIA and SAA (TS-IIA-PM) by self-assembling amphiphilic block copolymer PEG5000-SAA/PLA10000-APBA. The amphiphilic polymer was characterized by 1H NMR, FTIR, and alizarin red S competition tests. The ROS responsiveness of TS-IIA-PM was evidenced by time-course monitoring of particle size and morphology changes and drug release behavior in the presence of 1 mM H2O2. We found TS-IIA-PM was stable according to its critical micelle concentration and the unchanged particle sizes in 10% FBS for 7 days. The results of in vitro and in vivo tests revealed that TS-IIA-PM was safe and biocompatible. Furthermore, it was observed that TS-IIA and prodrug micelle could produce synergistic antiatherosclerotic effect based on the results of the antioxidant study, which was further confirmed by a series of pharmocodynamics studies, such as in vitro DiI-oxLDL uptake study, oil red O staining, cholesterol efflux study, inflammatory cytokine analysis, in vivo CD68 immunostaining, and lipid disposition staining studies. Collectively, TS-IIA-PM holds great potential for the safe and efficient codelivery of TS-IIA and SAA for synergistic antiatherosclerosis.

Synthesis and evaluation of novel and efficient Ni-based dual functional materials (DFMs) for integrated CO2 capture and hydrogenation

We report on the synthesis and evaluation of novel, highly active and stable bimetallic DFMs for simultaneous CO2 adsorption and subsequent hydrogenation to value added products. The DFMs contain various combinations of Ni (5–15 wt%) and Cu (5–15 wt%) with Na2O (5–15 wt%) as adsorbent supported on alumina (γ-Al2O3). The DFMs were synthesized via sequential incipient wetness impregnation method and were thoroughly characterized by combination of various surface sensitive and bulk sensitive analytical tools such as XRD, XPS, BET surface area, HR-TEM and H2-TPR. The DFMs were evaluated for CO2 capture and subsequent hydrogenation in a fixed-bed quartz tubular reactor connected with an online gas analyzer. The results demonstrated that at an operating temperature of 320℃, the DFM with a composition of 10 wt%Ni5wt%Cu/10 wt%Na2O.Al2O3 resulted in exceptionally high CO2 adsorption (310.84 μmol/g) and subsequent hydrogenation to methane (249.2 μmol CH4/gDFM). The XPS analysis revealed that this DFM contains comparatively larger percentage of highly ionized and/or induced Ni2+ as well as Cu+1 species. The results of H2-TPR also clearly indicated improvement in its reducibility. Moreover, the TEM analysis results revealed the presence of well-dispersed and smaller metal oxide particles in the bimetallic 10 wt%Ni5wt%Cu/10 wt%Na2O.Al2O3 DFM. In this regards, the exceptional high performance of the 10 wt%Ni5wt%Cu/10 wt%Na2O.Al2O3 DFM was attributed to the synergistic effects of the bimetallic combination of Ni with Cu resulting in enhanced physicochemical properties and thus demonstrated exceptionally higher performance.

SynBa: improved estimation of drug combination synergies with uncertainty quantification.

There exists a range of different quantification frameworks to estimate the synergistic effect of drug combinations. The diversity and disagreement in estimates make it challenging to determine which combinations from a large drug screening should be proceeded with. Furthermore, the lack of accurate uncertainty quantification for those estimates precludes the choice of optimal drug combinations based on the most favourable synergistic effect. In this work, we propose SynBa, a flexible Bayesian approach to estimate the uncertainty of the synergistic efficacy and potency of drug combinations, so that actionable decisions can be derived from the model outputs. The actionability is enabled by incorporating the Hill equation into SynBa, so that the parameters representing the potency and the efficacy can be preserved. Existing knowledge may be conveniently inserted due to the flexibility of the prior, as shown by the empirical Beta prior defined for the normalized maximal inhibition. Through experiments on large combination screenings and comparison against benchmark methods, we show that SynBa provides improved accuracy of dose-response predictions and better-calibrated uncertainty estimation for the parameters and the predictions. The code for SynBa is available at https://github.com/HaotingZhang1/SynBa. The datasets are publicly available (DOI of DREAM: 10.7303/syn4231880; DOI of the NCI-ALMANAC subset: 10.5281/zenodo.4135059).

Metabolomics revealed mechanism for the synergistic effect of sulbactam, polymyxin-B and amikacin combination against Acinetobacter baumannii.

The emergence of multidrug-resistant (MDR) Acinetobacter baumannii prompts clinicians to consider treating these infections with polymyxin combination. Metabolomic analysis was applied to investigate the synergistic effects of polymyxin-B, amikacin and sulbactam combination therapy against MDR A. baumannii harboring OXA-23 and other drug resistant genes. The drug concentrations tested were based on their clinical breakpoints: polymyxin-B (2 mg/L), amikacin (16 mg/L), polymyxin-B/amikacin (2/16 mg/L), and polymyxin-B/amikacin/sulbactam (2/16/4 mg/L). The triple antibiotic combination significantly disrupted levels of metabolites involved in cell outer membrane structure including fatty acids, glycerophospholipids, nucleotides, amino acids and peptides as early as 15 min after administration. Amikacin and polymyxin-B alone perturbed a large number of metabolites at 15 min and 1 h, respectively, but the changes in metabolites were short-lived lasting for less than 4 h. In contrast, the combination treatment disrupted a large amount of metabolites beyond 4 h. Compared to the double-combination, the addition of sulbactam to polymyxin-B/amikacin combination produce a greater disorder in A. baumannii metabolome that further confer susceptibility of bacteria to the antibiotics. The metabolomic analysis identified mechanisms responsible for the synergistic activities of polymyxin-B/amikacin/sulbactam against MDR A. baumannii.

The Potential Role of Epigallocatechin-3-Gallate (EGCG) in Breast Cancer Treatment

Breast cancer is one of the most diagnosed cancers worldwide, with an incidence of 47.8%. Its treatment includes surgery, radiotherapy, chemotherapy, and antibodies giving a mortality of 13.6%. Breast tumor development is driven by a variety of signaling pathways with high heterogeneity of surface receptors, which makes treatment difficult. Epigallocatechin-3-gallate (EGCG) is a natural polyphenol isolated as the main component in green tea; it has shown multiple beneficial effects in breast cancer, controlling proliferation, invasion, apoptosis, inflammation, and demethylation of DNA. These properties were proved in vitro and in vivo together with synergistic effects in combination with traditional chemotherapy, increasing the effectiveness of the treatment. This review focuses on the effects of EGCG on the functional capabilities acquired by breast tumor cells during its multistep development, the molecular and signal pathways involved, the synergistic effects in combination with current drugs, and how nanomaterials can improve its bioavailability on breast cancer treatment.

An End-to-end In-Silico and In-Vitro Drug Repurposing Pipeline for Glioblastoma.

Our study aims to address the challenges in drug development for glioblastoma, a highly aggressive brain cancer with poor prognosis. We propose a computational framework that utilizes machine learning-based propensity score matching to estimate counterfactual treatment effects and predict synergistic effects of drug combinations. Through our in-silico analysis, we identified promising drug candidates and drug combinations that warrant further investigation. To validate these computational findings, we conducted in-vitro experiments on two GBM cell lines, U87 and T98G. The experimental results demonstrated that some of the identified drugs and drug combinations indeed exhibit strong suppressive effects on GBM cell growth. Our end-to-end pipeline showcases the feasibility of integrating computational models with biological experiments to expedite drug repurposing and discovery efforts. By bridging the gap between in-silico analysis and in-vitro validation, we demonstrate the potential of this approach to accelerate the development of novel and effective treatments for glioblastoma.

SMILESynergy: Anticancer drug synergy prediction based on Transformer pre-trained model

The synergistic effect of drug combinations can solve the problem of acquired resistance to single drug therapy and has great potential for the treatment of complex diseases such as cancer. In this study, to explore the impact of interactions between different drug molecules on the effect of anticancer drugs, we proposed a Transformer-based deep learning prediction model-SMILESynergy. First, the drug text data-simplified molecular input line entry system (SMILES) were used to represent the drug molecules, and drug molecule isomers were generated through SMILES Enumeration for data augmentation. Then, the attention mechanism in the Transformer was used to encode and decode the drug molecules after data augmentation, and finally, a multi-layer perceptron (MLP) was connected to obtain the synergy value of the drugs. Experimental results showed that our model had a mean squared error of 51.34 in regression analysis, an accuracy of 0.97 in classification analysis, and better predictive performance than the DeepSynergy and MulinputSynergy models. SMILESynergy offers improved predictive performance to assist researchers in rapidly screening optimal drug combinations to improve cancer treatment outcomes.

The Synergistic Effect of Combination of Pentagamavunone-1 with Diosmin, Galangin, and Piperine in WiDr Colon Cancer Cells: <i>In vitro</i> and Target Protein Prediction

Pentagamavunone-1 (PGV-1) is a curcumin analog with a prominent anti-cancer potency in vitro and in vivo for several cancer types, including colon cancer. Combining PGV-1 with natural compounds such as diosmin, galangin, and piperine can enhance its effectiveness due to their promising chemoprevention properties. We aimed to evaluate the effectiveness of combining PGV-1 with diosmin, galangin, or piperine for colon cancer by using in vitro and bioinformatic approaches to predict their target proteins. WiDr cells were used as a model for colon adenocarcinoma (COAD). The cell viability under a single or combination treatment of PGV-1 and diosmin, galangin, or piperine was evaluated using direct counting by the trypan blue exclusion test. SwissTargetProtein, UALCAN, and OncoLnc were utilized to predict target proteins of the compounds in COAD, the expression level of target proteins in COAD, and the survival rate of patients with overexpressed target proteins, respectively. The IC50 values for PGV-1, diosmin, galangin, and piperine were 2.8´10-2 µg/mL, 81 µg/mL, 7 µg/mL, and 172 µg/mL, respectively. All the tested natural compounds showed synergistic effects when combined with PGV-1 at low concentrations. Eleven proteins that were overexpressed in COAD were identified as potential targets. Overlapped predicted targets of PGV-1 and galangin or piperine were CDK1, MET, and TOP2A. The high expression of another set of predicted target proteins, SCD, CA9, and SQLE, led to lower survival rates in COAD patients. We concluded that combinations of PGV-1 with natural compounds can synergistically enhane its anti-cancer activity for colon cancer.

Synergistic Effects of Essential Oils and Antibiotics Against Some Bacterial Strains

The emergence of antibiotics resistances become an alarming situation due to the resurgence of cases. Scientific community explore therapeutics alternatives, including essentials oils and their combination with antibiotics. The designed study aimed to evaluate the combined effects of essentials oils from Drypetes Gosswelleri, Echinops giganteus, Melaleuca leucadendron essentials oils and antibiotics against strains implicated in infectious deseases. The antibacterial effect of essentials oils and antibiotics (Ciprofloxacine and Ceftriaxone) was carried out against Pseudomonas aeruginosa, Klebsiella pnemoneae, Salmonella enteritidis, Staphylococcus aureus and Bacillus cereus strains using the microdilution method. The synergistic effects were studied by the isobologram method to conclude on the interaction type. The results revealed that the essential oils were active against all the tested bacteria. Drypetes Gosswelleri EO showed the strongest activity with MICs ranging from 1.46 μg/mL to 11.71 µg/mL, followed by Echinops giganteus essential oil with MICs ranging from 2.92 µg/mL to 23.43 µg/mL and Melaleuca leucadendron had the lowest activity with MICs ranging from 5.88µg/mL to 750µg/mL. The combinations realized between Drypetes Gosswelleri and Echinops giganteus EOs and with two antibiotics use to evaluate the interaction type agains Salmonella enteritidis and Staphylococcus aureus. MICs obtained with the combinations are lower than those obtained with the EOs and antibiotics tested individually. The isobolograms plotted inform about a synergistic effects of combinations made with Drypetes Gosswelleri, Echinops giganteus EOs, Ciprofloxacin and Ceftriaxone against S. enteritidis and S. aureus strains. Based on the results obtained, the combinations between EOs and the antibiotocs, represent an interesting therapeutic alternative.
 Keywords: antibacterial, essential oil, combination, isobolograms, synergistics, Minimale Inhibitory Concentration, Minimale Bactericidal Concentration.

Encapsulation of Nano-Bortezomib in Apoptotic Stem Cell-Derived Vesicles for the Treatment of Multiple Myeloma.

Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play critical roles in cell-cell communication and tissue homeostasis, and have numerous therapeutic uses including serving as carriers for nanodrug delivery. There are multiple ways to load EVs with nanodrugs, such as electroporation, extrusion, and ultrasound. However, these approaches may have limited drug-loading rates, poor EV membrane stability, and high cost for large-scale production. Here, it is shown that apoptotic mesenchymal stem cells (MSCs) can encapsulate exogenously added nanoparticles into apoptotic vesicles (apoVs) with a high loading efficiency. When nano-bortezomib is incorporated into apoVs in culture-expanded apoptotic MSCs, nano-bortezomib-apoVs show a synergistic combination effect of bortezomib and apoVs to ameliorate multiple myeloma (MM) in a mouse model, along with significantly reduced side effects of nano-bortezomib. Moreover, it is shown that Rab7 regulates the nanoparticle encapsulation efficiency in apoptotic MSCs and that activation of Rab7 can increase nanoparticle-apoV production. In this study, a previously unknown mechanism to naturally synthesize nano-bortezomib-apoVs to improve MM therapy is revealed.