Development Of Multiple Drug Resistance Research Articles

Advances in Chitosan-Based Smart Hydrogels for Colorectal Cancer Treatment

Despite advancements in early detection and treatment in developed countries, colorectal cancer (CRC) remains the third most common malignancy and the second-leading cause of cancer-related deaths worldwide. Conventional chemotherapy, a key option for CRC treatment, has several drawbacks, including poor selectivity and the development of multiple drug resistance, which often lead to severe side effects. In recent years, the use of polysaccharides as drug delivery systems (DDSs) to enhance drug efficacy has gained significant attention. Among these polysaccharides, chitosan (CS), a linear, mucoadhesive polymer, has shown promise in cancer treatment. This review summarizes current research on the potential applications of CS-based hydrogels as DDSs for CRC treatment, with a particular focus on smart hydrogels. These smart CS-based hydrogel systems are categorized into two main types: stimuli-responsive injectable hydrogels that undergo sol-gel transitions in situ, and single-, dual-, and multi-stimuli-responsive CS-based hydrogels capable of releasing drugs in response to various triggers. The review also discusses the structural characteristics of CS, the methods for preparing CS-based hydrogels, and recent scientific advances in smart CS-based hydrogels for CRC treatment.

Adaptive Resilience: Unraveling the Path of Heavy Metal Tolerance in Multidrug Resistant Pathogens

Co-existence of heavy metal tolerance and antibiotic resistance in bacterial strains pose potential threats to human health and environment. In recent decades, heavy metal pollution has caused selective pressure that leads to the development of multiple drug resistance among bacterial populations. Escherichia coli, Pseudomonas aeruginosa and Staphylococcus cohnii were used in the study. Out of 8 antibiotics tested, it was observed that E.coli was resistant to four, S.cohnii and P. aeruginosa were resistant only to three antibiotics. The isolates were found to grow at high concentration of copper (CuSO4) and varying degrees of chromium (K2Cr2O7) with all the three being sensitive to mercuric chloride (HgCl2). E. coli, S. cohnii and P. aeruginosa were inhibited at 0.84±0.05, 6.79±0.07 and 2.54±0.02 μM ml-1 respectively by chromium salt; similarly, E. coli, S. cohnii and P. aeruginosa had a MIC of 1.56±0.03 μM ml-1, 1.25±0.05 μM ml-1 and 1.56±0.05μM ml-1 and for copper, E. coli, S. cohnii and P. aeruginosa had a MIC of 8.20±0.05, 9.20±0.01, 7.18±0.05μM ml-1 respectively. Further studies were carried out by agarose gel electrophoresis and SDS-PAGE for the characterization of R-plasmid and heavy metal stress protein among the isolated bacteria. The qPCR was used for identification of antimicrobial resistant genes. A phylogenetic study was performed on S. cohnii to understand its evolutionary traits. The results provide insight into the co-occurrence of antibiotic resistance and heavy metal tolerance in clinically important bacterial communities, which may create severe health issues in the coming decades.

NCI677397 targeting USP24-mediated induction of lipid peroxidation induces ferroptosis in drug-resistant cancer cells.

Cancer represents a profound challenge to healthcare systems and individuals worldwide. The development of multiple drug resistance is a major problem in cancer therapy and can result in progression of the disease. In our previous studies, we developed small-molecule inhibitors targeting ubiquitin-specific peptidase 24 (USP24) to combat drug-resistant lung cancer. Recently, we found that the USP24 inhibitor NCI677397 induced ferroptosis, a type of programmed cell death, in drug-resistant cancer cells by increasing lipid reactive oxygen species (ROS) levels. In the present study, we investigated the molecular mechanisms and found that the targeting of USP24 by NCI677397 increased gene expression of most lipogenesis-related genes, such as acyl-CoA synthetase long-chain family member 4 (ACSL4), and activated autophagy. In addition, the activity of several antioxidant enzymes, such as glutathione peroxidase 4 (GPX4) and dihydrofolate reductase (DHFR), was inhibited by NCI677397 treatment via an increase in protein degradation, thereby inducing lipid ROS production and lipid peroxidation. In summary, we demonstrated that NCI677397 induced a marked increase in lipid ROS levels, subsequently causing lipid peroxidation and leading to the ferroptotic death of drug-resistant cancer cells. Our study provides new insights into the clinical use of USP24 inhibitors as ferroptosis inducers (FINs) to block drug resistance during chemotherapy.

Nanomaterials as targeted delivery system of therapeutics for inhibition of cancer

Cancer, a disease with complex pathological process, is the principal cause of mortality and morbidity throughout the world. Conventional chemotherapy faces drawbacks regarding its low bioavaiability, insolubility, high dose requirements, low therapeutic indices, cytotoxicity, multiple drug resistance-development, biological barriers related obstruction, and non-specific targeting. Cancer drug resistance includes over-expression of drug efflux transporters, hypoxic environment, and defective apoptotic pathways. To overcome these discrepancies, a lot of nanomaterials (NMs), as emerging delivery system, have attracted attention for carrying and delivering therapeutics to the desired sites of interest. For improving the targeting potential of the anticancer cargos, NMs are optimized for their sizes, shapes, and surfaces for enhancing their circulation time and targeting efficiency. The NMs through encapsulation or conjugation of cargos with ligands may target them to the cancer site/s with enhanced therapeutic efficacy in a controlled release manner. Generally, NMs, as cancer therapy, are utilized to target cancer cells, tumor microenvironment, and immune system mainly through enhanced permeability and retention (EPR) effect¸­ stimuli-responsive targeting or modifying their surfaces with targeting ligands such as transferin, integrins, sugar, folic acid and antibodies for the enhancement of tissue targeting recognition and their internalization. This review demonstrates mainly the biomedical applications of NMs as delivery vehicles or systems functionalized with ligands and therapeutic agents to target cancer cells / tissues passively, actively or physically with higher inhibitory therapeutic efficacies against cancer.
 Keywords: Cancer; Conventional chemotherapy; Nanomaterials; Biomedical applications; Therapeutic targeting; Inhibitory therapeutic efficacies

Effect of Polyunsaturated Fatty Acids on Temozolomide Drug-Sensitive and Drug-Resistant Glioblastoma Cells.

Glioblastomas (GBMs) are notoriously difficult to treat, and the development of multiple drug resistance (MDR) is common during the course of the disease. The polyunsaturated fatty acids (PUFAs) gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have been reported to improve MDR in several tumors including breast, bladder, and leukaemia. However, the effects of PUFAs on GBM cell MDR are poorly understood. The present study investigated the effects of PUFAs on cellular responses to temozolomide (TMZ) in U87MG cells and the TMZ-resistant (TMZR) cells derived from U87MG. Cells were treated with PUFAs in the absence or presence of TMZ and dose-response, viable cell counting, gene expression, Western blotting, flow cytometry, gas chromatography-mass spectrometry (GCMS), and drug efflux studies were performed. The development of TMZ resistance caused an increase in ABC transporter ABCB1 and ABCC1 expression. GLA-, EPA-, and DHA-treated cells had altered fatty acid composition and accumulated lipid droplets in the cytoplasm. The most significant reduction in cell growth was seen for the U87MG and TMZR cells in the presence of EPA. GLA and EPA caused more significant effects on ABC transporter expression than DHA. GLA and EPA in combination with TMZ caused significant reductions in rhodamine 123 efflux from U87MG cells but not from TMZR cells. Overall, these findings support the notion that PUFAs can modulate ABC transporters in GBM cells.

Abstract B006: Does TFPI1 drive development of multiple drug resistant cancer and can the anaphase promoting complex prevent it

Abstract Chemotherapy is often rendered ineffective by the development of multiple drug resistance (MDR). Given time MDR occurs almost universally and once developed applies in a non-specific manner. The lack of MDR specificity means many drugs, including those a patient has no pervious exposure to, are affected which limits treatment options. The goal of this research is to show nuclear localized tissue factor pathway inhibitor 1 (TFPI1) plays a driving role in development of MDR, and that the Anaphase Promoting Complex (APC) is capable of inhibiting MDR by targeting TFPI1 for degradation. A coagulation regulator, TFPI1 normally inhibits the tissue factor pathway to prevent blood clot formation. However, TFPI1 is highly elevated in many types of MDR cancer where we believe it mediates resistance development. Previous work in our lab has shown plasmid overexpression of TFPI1 induces MDR in MCF7 breast cancer cells, in MDR cells TFPI1 does not localize to the cell surface but instead to the nucleus, and a putative TFPI1 nuclear localization sequence (NLS) was identified. To confirm the putative NLS is required for TFPI1’s localization to nucleus, and subsequent MDR development, NLS mutant or wild type TFPI1-GFP were overexpressed in MCF7 cells. Localization of TFPI1-GFP was observed using widefield and confocal microscopy. Wild type TFPI1-GFP localized to the nucleus while the NLS mutant TFPI1 did not. These results help to confirm the putative NLS and its importance to TFPI1s role in MDR development. The APC is a nuclear E3 ubiquitin ligase and highly conserved regulator of cell cycle progression. Defects in APC function are associated with reduced longevity and cancer. Other work in our lab focuses on the APC’s role in longevity using a yeast model. However, we believe the APC also plays a role in TFPI1’s promotion of MDR. Our observations suggest APC dysfunction exists within MDR cancer cells where APC substrates accumulate, as does TFPI1. We hypothesize that nuclear TFPI1 is an APC substrate, and that APC activation will result in TFPI1 degradation slowing MDR development. Our lab has isolated several small peptides we believe bind and activate the APC, and have used these peptides in conjugation with known APC activators such as Mad2 Inhibitor-1 (M2I-1) to show that APC activation is capable of reducing TFPI1 abundance in MCF7 cells treated with the chemotherapeutic Doxorubicin (Dox). These results suggest TFPI1 is an APC substrate. To summarize, we believe TFPI1 drives development of MDR cancer, for which TFPI1’s accumulation within the nucleus is important. We have shown TFPI1’s NLS is required for localization of the protein to the nucleus, and activation of the APC reduces nuclear accumulation of TFPI1. Moving forward our goal is to demonstrate the effect TFPI1 NLS knockout and APC activation have on the development of MDR in MCF7 cells undergoing drug selection with Dox. By exploring TFPI1’s role in MDR we may elucidate means to slow resistance development and extend chemotherapy effectiveness. Citation Format: Mathew Lubachowski, Troy Harkness. Does TFPI1 drive development of multiple drug resistant cancer and can the anaphase promoting complex prevent it [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B006.

Ultrasound-Responsive Nanocarriers for Breast Cancer Chemotherapy.

Breast cancer is the most common type of cancer and it is treated with surgical intervention, radiotherapy, chemotherapy, or a combination of these regimens. Despite chemotherapy’s ample use, it has limitations such as bioavailability, adverse side effects, high-dose requirements, low therapeutic indices, multiple drug resistance development, and non-specific targeting. Drug delivery vehicles or carriers, of which nanocarriers are prominent, have been introduced to overcome chemotherapy limitations. Nanocarriers have been preferentially used in breast cancer chemotherapy because of their role in protecting therapeutic agents from degradation, enabling efficient drug concentration in target cells or tissues, overcoming drug resistance, and their relatively small size. However, nanocarriers are affected by physiological barriers, bioavailability of transported drugs, and other factors. To resolve these issues, the use of external stimuli has been introduced, such as ultrasound, infrared light, thermal stimulation, microwaves, and X-rays. Recently, ultrasound-responsive nanocarriers have become popular because they are cost-effective, non-invasive, specific, tissue-penetrating, and deliver high drug concentrations to their target. In this paper, we review recent developments in ultrasound-guided nanocarriers for breast cancer chemotherapy, discuss the relevant challenges, and provide insights into future directions.

Activation of the Anaphase Promoting Complex Reverses Multiple Drug Resistant Cancer in a Canine Model of Multiple Drug Resistant Lymphoma.

Simple SummaryMultiple drug resistant cancers develop all too soon in patients who received successful cancer treatment. A lack of treatment options often leaves palliative care as the last resort. We tested whether the insulin sensitizer, metformin, known to have anti-cancer activity, could impact canines with drug resistant lymphoma when added to chemotherapy. All canines in the study expressed protein markers of drug resistance and within weeks of receiving metformin, the markers were decreased. A microarray was performed, and from four canines assessed, a common set of 290 elevated genes were discovered in tumor cells compared to control cells. This cluster was enriched with genes that stall the cell cycle, with a large component representing substrates of the Anaphase Promoting Complex (APC), which degrades proteins. One canine entered partial remission. RNAs from this canine showed that APC substrates were decreased during remission and elevated again during relapse, suggesting that the APC was impaired in drug resistant canines and restored when remission occurred. We validated our results in cell lines using APC inhibitors and activators. We conclude that the APC may be a vital guardian of the genome and could delay the onset of multiple drug resistance when activated.Like humans, canine lymphomas are treated by chemotherapy cocktails and frequently develop multiple drug resistance (MDR). Their shortened clinical timelines and tumor accessibility make canines excellent models to study MDR mechanisms. Insulin-sensitizers have been shown to reduce the incidence of cancer in humans prescribed them, and we previously demonstrated that they also reverse and delay MDR development in vitro. Here, we treated canines with MDR lymphoma with metformin to assess clinical and tumoral responses, including changes in MDR biomarkers, and used mRNA microarrays to determine differential gene expression. Metformin reduced MDR protein markers in all canines in the study. Microarrays performed on mRNAs gathered through longitudinal tumor sampling identified a 290 gene set that was enriched in Anaphase Promoting Complex (APC) substrates and additional mRNAs associated with slowed mitotic progression in MDR samples compared to skin controls. mRNAs from a canine that went into remission showed that APC substrate mRNAs were decreased, indicating that the APC was activated during remission. In vitro validation using canine lymphoma cells selected for resistance to chemotherapeutic drugs confirmed that APC activation restored MDR chemosensitivity, and that APC activity was reduced in MDR cells. This supports the idea that rapidly pushing MDR cells that harbor high loads of chromosome instability through mitosis, by activating the APC, contributes to improved survival and disease-free duration.

Studies on evaluation of antibacterial activities of some cultivated mushrooms against human pathogenic bacteria

Mushrooms have been used as source of nutritive food and medicine since ancient time. The indiscriminate utilization of modern antibiotic drugs has caused the development of multiple drug resistance in pathogenic microbes. The antimicrobial properties of herbs and mushrooms have proved to be fruitful in getting rid of from the problem of multiple drug resistance. In this study, the antibacterial activity of acetone, aqueous and methanol extracts of Agaricus bisporus, Calocybe indica, Flammulina velutipes, Pleurotus florida, and Volvariella volvacea were investigated against human pathogenic bacteria. The antimicrobial activity  of these mushrooms were evaluated following the agar well diffusion method against Bacillus cereus, Staphylococcus aureus, Listeria monocytogenes and gram negative bacteria Shigella dysenteriae, Salmonella typhi and Escherichia coli. All the studied mushrooms displayed considerable antibacterial activity against all the pathogenic bacteria under study and it was found to be extraction solvent dependent. The zones of growth inhibition of 12.26-14.80 mm in Agaricus bisporus, 12.84-15.31mm in Calocybe indica, 13.82-16.17 mm Flammulina velutipes, 12.2-14.80 mm in Pleurotus florida, and 12.34-15.84 mm in Volvariella volvacea were recorded in acetone extract. The zones of growth inhibition of 10.73-11.23 mm in Agaricus bisporus, 10.63-12.62 mm in Calocybe indica, 12.50-13.84 mm Flammulina velutipes, 11.14-11.97 mm in Pleurotus florida, and 11.51-12.31 mm in Volvariella volvacea were observed in aqueous extract. The zone of inhibition observed in methanol extract were 13.06-14.93 mm in Agaricus bisporus, 11.96-14.01 mm in Calocybe indica, 12.01-13.41 mm Flammulina velutipes, 13.02-13.74 mm in Pleurotus florida, and 13.32-15.21 mm in Volvariella volvacea. The minimum inhibitory concentration (MIC) of acetone extract ranged from 0.3125 µg/100µl-0.625 µg/100µl, aqueous extract 0.625 µg/100µl-2.5 µg/100µl and methanol extract 0.3125 µg/100µl-1.25 µg/100µl. The results emphasize that there is a need for further studies to isolate and characterize the bioactive compounds present in these cultivated mushrooms so that their antibacterial potential can be used to develop effective drugs against these human pathogenic bacterial strains.Keywords: Mushrooms, antibacterial, minimum inhibitory concentration, zone of inhibition.

Meta analysis of bioactive compounds, miRNA, siRNA and cell death regulators as sensitizers to doxorubicin induced chemoresistance.

Cancer has presented to be the most challenging disease, contributing to one in six mortalities worldwide. The current treatment regimen involves multiple rounds of chemotherapy administration, alone or in combination. The treatment has adverse effects including cardiomyopathy, hepatotoxicity, and nephrotoxicity. In addition, the development of resistance to chemo has been attributed to cancer relapse and low patient overall survivability. Multiple drug resistance development may be through numerous factors such as up-regulation of drug transporters, drug inactivation, alteration of drug targets and drug degradation. Doxorubicin is a widely used first line chemotherapeutic drug for a myriad of cancers. It has multiple intracellular targets, DNA intercalation, adduct formation, topoisomerase inhibition, iron chelation, reactive oxygen species generation and promotes immune mediated clearance of the tumor. Agents that can sensitize the resistant cancer cells to the chemotherapeutic drug are currently the focus to improve the clinical efficiency of cancer therapy. This review summarizes the recent 10-year research on the use of natural phytochemicals, inhibitors of apoptosis and autophagy, miRNAs, siRNAs and nanoformulations being investigated for doxorubicin chemosensitization.

APPLICATION OF NANOANTIBIOTICS APPROACH AGAINST ANTI-BACTERIAL RESISTANCE

Despite the fact that we live in an era with unique and advanced technology for revealing underlying molecularly creating new drugs and disease mechanisms, infectious illnesses remain one of the world's major health issues. Antimicrobial agents now available against pathogenic microorganisms are insufficient to combat the problems posed by novel multidrug-resistant (MDR) infections. Antimicrobial drug restrictions are producing negative side effects and the development of multiple drug resistance. Drug resistance will necessitate the use of high-dose antibiotics, resulting in severe toxicity and the development of new medicines. Nanoantibiotics, a new type of antimicrobial agent that combines antimicrobial compounds with nanoparticles, has been created to solve these shortcomings. Additionally, previous reports stated that the pharmacokinetics profiles and have quicker ingestion in circulatory framework. In this subject, we will clarify the various sorts of nanoantibiotics, their instrument of activity, key targets and medication discharge components. We will likewise portray some significant microbial elements that will influence the activity of nanoantibiotics.

Engineering of anticancer drugs entrapped polymeric nanoparticles for the treatment of colorectal cancer therapy

Traditional chemotherapeutic agents have been successfully used to treat cancers, although their many disadvantages include poor solubility, high dosage needs, severe side effects, low therapeutic indices, development of multiple drug resistance, and non-specific targeting of cancer cells. In this study, Methotrexate (MEX) and curcumin (CUR) were incorporated into the triblock copolymer poly(lactic-co-glycolic acid) (PLGA)–poly(ethylene glycol) (PEG)–PLGA to achieve synergism in the treatment of colorectal cancer. Nanoparticle-based combination treatments for colorectal cancer can be developed using this remarkably symmetric synthetic strategy. The particles were visualized by high-resolution transmission microscopy (HR-TEM), and their size and polydispersity were determined using dynamic light scattering. Without a blast of impact, MEX and CUR were released gently from the polymeric nanoparticle system. CUR/MEX@NPs also demonstrated dose-dependent cytotoxic effects on SW1417 and CL40 cell lines, with a higher apoptosis ratio than free MEX and CUR. According to the in vitro cellular uptake analysis, cancer cells absorbed the polymeric nanoparticles more readily. From the fluorescence experiment, nanomaterials promoted cell death in the SW1417 and CL40 cell lines. Additionally, in vivo systemic toxicity and in vitro findings support the biocompatibility of CUR/MEX@NPs. Furthermore, these nanomaterials cause apoptosis in cancer cells. From these findings, CUR/MEX@NPs exhibit the potential to be successfully utilized to treat colorectal cancer.

One-step self-assembly of biogenic Au NPs/PEG-based universal coatings for antifouling and photothermal killing of bacterial pathogens

Schematic representation of the antifouling and photothermal antibacterial applications of PDMS-TA-PEG-Au surface. • A gold/polymer coating was developed in an one-pot process. • The gold/polymer coating can be deposited on surfaces in a substrate-independent manner. • The gold/polymer coating exhibits good antifouling and photo-induced antibacterial properties. • The gold/polymer coating shows good anti-infection property in vivo . Severe medical device-associated infections caused by pathogenic bacteria have become an immediate threat to global public health, mainly because of the development of multiple drug resistance (MDR). Relevant design of functionalized biomaterials are thus essential to remit or mitigate the medical device-associated infections. In the present work, we developed a strategy of combining antifouling and photothermal therapy (PTT) in a single platform for antibacterial applications. The polydimethylsiloxane (PDMS) surface was modified with poly(ethylene glycol) (PEG) and tannic acid-reduced gold nanoparticles (Au@TA NPs) for better photothermal and antifouling performance. PEG facilitates the rapid self-assembly of Au@TA NPs on the surface to form a stable Au@TA NPs/PEG (TA-PEG-Au) layer. The functionalized surface with antifouling and antibacterial properties arise from the inherent fouling resistance of PEG and photothermal conversion of Au NPs. The TA-PEG-Au coating exhibits remarkable antifouling performance to bacterial adhesion and excellent antibacterial property under near-infrared (NIR) irradiation both in vitro and in vivo . The antibacterial TA-PEG-Au coatings also show low cytotoxicity. The present work provides an efficient strategy for the design of high-performance antifouling and antibacterial materials to fight against medical device-associated infections.

The APEX1/miRNA-27a-5p axis plays key roles in progression, metastasis and targeted chemotherapy of gastric cancer

Gastric cancer (GC) presents a challenge for conventional therapeutics due to low targeting specificity and subsequent elicitation of multiple drug resistance (MDR). As an essential enzyme for DNA repair, apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) exhibits multiple functions to affect cancer malignancy and is excessively expressed in GC. However, the roles APEX1 and its inhibitor miR-27a-5p play in modulating GC progression and MDR development remains unclear. Here, we verified APEX1 as a target of miR-27a-5p and subsequently established the APEX1-deleted SGC-7901 cell line by CRISPR/Cas9 editing. The roles of the APEX1/miR-27a-5p axis in GC progression, metastasis and doxorubicin (DOX) resistance were explored by the targeted chemotherapy facilitated by a GC-specific peptide (GP5) functionalized liposomal drug delivery formulation (GP5/Lipo/DOX/miR-27a-5p). The results showed that APEX1 deletion distinctly attenuated cell growth and metastatic properties in GC, and also sensitized GC cells to DOX. Notably, miR-27a-5p was validated as a suppressor of APEX1-dependent GC development and DOX resistance by a RAS/MEK/FOS and PTEN/AKT/SMAD2 pathway-dependent manner. The altered expression of epithelial-mesenchymal transition (EMT) signatures and signal pathway proteins in the APEX1-deleted cells implied that APEX1 potentially enhances DOX resistance of GC cells by altering the regulation of MAPK and AKT pathways, leading to compromised efficacy of chemotherapy or by initiating additional DNA damage response pathways. Taken together, these findings revealed that as a novel therapeutic target, APEX1/miR-27a-5p axis plays essential roles in modulating the GC development and MDR, and the GC targeted drug delivery formulation presents a strategic reference for the future designation of chemotherapeutics study.

Combination of coumarin and doxorubicin induces drug-resistant acute myeloid leukemia cell death

BackgroundChemotherapy remains to be the method of choice used by clinicians to treat acute myeloid leukemia (AML) patients. However, the most common problem usually faced in the course of treatment is multidrug resistance (MDR). Nowadays, combination therapy involving natural products as adjuvant therapy to chemotherapy and radiotherapy has been used for many of health problems. Coumarin is a natural compound with known chemotherapeutic activity, as well as other pharmacological properties. We focused on the combination of coumarin and doxorubicin in overcoming of drug-resistance in acute myeloid leukemia. MethodsCell viability, Apoptotic and necrotic cell death with FACS, oxidative stress detection, and protein expression analysis were used in this study. ResultsCoumarin as a single drug exerts a significant cell death on Human acute myeloid leukemia (HL60); however, it does not show the same effect on drug-resistant acute myeloid leukemia (HL60/ADR). Comparing the effects of doxorubicin and coumarin as single drugs versus a combination of coumarin and doxorubicin showed a significant apoptotic cell death. ConclusionIn AML patients, the development of multiple drug resistance (MDR) is the biggest challenge in treating AML patients. Combination therapy with coumarin may be a good choice to overcome the drug resistance in AML patients.

Identification of Lead Compounds against Scm (fms10) in Enterococcus faecium Using Computer Aided Drug Designing.

(1) Background: Enterococcus faecium DO is an environmental microbe, which is a mesophilic, facultative, Gram-positive, and multiple habitat microorganism. Enterococcus faecium DO is responsible for many diseases in human. The fight against infectious diseases is confronted by the development of multiple drug resistance in E. faecium. The focus of this research work is to identify a novel compound against this pathogen by using bioinformatics tools and technology. (2) Methods: We screened the proteome (accession No. PRJNA55353) information from the genome database of the National Centre for Biotechnology Information (NCBI) and suggested a potential drug target. I-TASSER was used to predict the three-dimensional structure of the protein, and the structure was optimized and minimized by different tools. PubChem and ChEBI were used to retrieve the inhibitors. Pharmacophore modeling and virtual screening were performed to identify novel compounds. Binding interactions of compounds with target protein were checked using LigPlot. pkCSM, SwissADME, and ProTox-II were used for adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. (3) Results: Novel selected compounds have improved absorption and have better ADMET properties. Based on our results, the chemically identified inhibitor ZINC48942 targeted the receptor that can inhibit the activity of infection in E. faecium. This research work will be beneficial for the scientific community and could aid in the design of a new drug against E. faecium infections. (4) Conclusions: It was observed that novel compounds are potential inhibitors with more efficacy and fewer side effects. This research work will help researchers in testing and identification of these chemicals useful against E. faecium.

Understanding of Colistin Usage in Food Animals and Available Detection Techniques: A Review.

Simple SummaryColistin is a last resort drug for the treatment of infection caused by multidrug-resistant Gram-negative bacteria. Different studies have uncovered the negative impact of colistin consumption in animals. Therefore, it has become essential to monitor the dosing regimens of colistin and assess their negative effects. The current review intends to provide brief information of colistin usage and its associated negative impact and discuss available techniques to detect colistin in animal-based food so that effective preventive measures can be taken to minimize the health risks in both animals and humans.Progress in the medical profession is determined by the achievements and effectiveness of new antibiotics in the treatment of microbial infections. However, the development of multiple-drug resistance in numerous bacteria, especially Gram-negative bacteria, has limited the treatment options. Due to this resistance, the resurgence of cyclic polypeptide drugs like colistin remains the only option. The drug, colistin, is a well-known growth inhibitor of Gram-negative bacteria like Acinetobacter baumanni, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Technological advancements have uncovered the role of the mcr-1(mobilized colistin resistance) gene, which is responsible for the development of resistance in Gram-negative bacteria, which make them distinct from other bacteria without this gene. Additionally, food animals have been determined to be the reservoir for colistin resistance microbes, from which they spread to other hosts. Due to the adverse effects of colistin, many developed countries have prohibited its usage in animal foods, but developing countries are still using colistin in animal food production, thereby imposing a major risk to the public health. Therefore, there is a need for implementation of sustainable measures in livestock farms to prevent microbial infection. This review highlights the negative effects (increased resistance) of colistin consumption and emphasizes the different approaches used for detecting colistin in animal-based foods as well as the challenges associated with its detection.

Cervical cancer: a meta-analysis, therapy and future of nanomedicine.

Cervical cancer is one of the leading causes of female death, with an annual mortality rate exceeding 200,000 in developing communities. Despite the past decade bearing witness to a reduction in cervical cancer cases throughout developed countries, the prevalence in developing countries continues to rapidly rise. The increase in cervical cancer cases is attributed to the lack of financial resources and the unavoidable risk factors of the disease. Traditional means of anticancer therapy are compromised by reduced drug potency, non-specificity, negative side effects and the development of multiple drug resistance (MDR), which leads to a decrease in the long-term anticancer therapeutic efficacy. Recent advances in nanomedicine have elucidated the potential of nanoparticles to reduce the side effects and improve the survival rate of patients, by enhancing selective delivery and uptake of photosensitive, therapeutic and genetic material to cervical cancer cells, thereby enhancing antitumour efficiency. This review paper analyses the risk factors and epidemiology of cervical cancer globally, especially in developing communities, whilst demonstrating the enhanced anticancer treatment using selected nanoparticles.

Cholesterol metabolism in drug‑resistant cancer (Review).

Cancer represents a severe challenge to healthcare systems and individuals worldwide. The development of multiple drug resistance is a major issue regarding cancer therapy, which can result in the progression of disease. Cholesterol is a major constituent of cell membranes and participates in the regulation of several cellular processes, such as cell growth, proliferation, differentiation, survival and apoptosis. Numerous studies have provided correlative support for a role of cholesterol in cancer development and drug resistance. In the present review, recent insights into the regulation of cholesterol metabolism, the association between cholesterol and the efficacy of antitumor agents in preclinical studies, as well as the possible mechanisms through which cholesterol influences drug resistance, are summarized. Furthermore, the clinical relevance of cholesterol to the development of cancer, as well as strategies targeting cholesterol for therapeutic intervention are detailed. Collectively, studies on various types of cancer have suggested that increased cholesterol levels promote resistance to chemotherapeutic drugs in cancer through a variety of mechanisms, and that the depletion of cholesterol using statins significantly enhances the sensitivity of the therapeutic agents. However, additional studies are required to enhance the current understanding of the involvement of cholesterol in the development of drug‑resistant cancer.

Self-Assembly Nanoparticles for Overcoming Multidrug Resistance and Imaging-Guided Chemo-Photothermal Synergistic Cancer Therapy.

Background and PurposeThe development of multiple drug resistance (MDR) to chemotherapy and single modal therapy remains unsatisfied for the eradication of tumor, which are major obstacles in cancer therapy. This novel system with excellent characteristics for inhibition of P-glycoprotein (P-gp), and for near-infrared fluorescence (NIRF) imaging-guided chemo-photothermal therapy (PTT), has been identified as a promising way to MDR and achieve synergistic cancer therapy.MethodsIn this study, we successfully synthesized a multifunctional theranostic system, which was developed through FDA-approved self-assembling drugs, which contain anticancer drug doxorubicin (Dox), imaging and high photothermal conversion drug indocyanine green (ICG) and P-gp regulator TPGS (the system named T/Dox-ICG). We studied the characterization of T/Dox-ICG NPs, including the TEM, SEM, DLS, UV-vis-NIR, zeta potential, CLSM, in vitro FL imaging, in vitro photothermal effect, in vitro Dox and ICG release. We used CLSM to verify the location of intracellular distribution of Dox in SCG 7901/VCR cells, Western blot was performed to demonstrate the TPGS-mediated inhibition of P-gp. And, the cytotoxicity of materials against SCG 7901/VCR cells was studied by the MTT assay.ResultsThe TEM showed the T/Dox-ICG NPs had good monodispersity with diameters of 19.03 nm, Dox and ICG could be released constantly from T/Dox-ICG NPs in vitro. In vitro cell experiments demonstrated higher Dox accumulation and retention in the nucleus. Western blot showed TPGS could obviously inhibit the expression of P-gp. In vitro cytotoxicity assay showed more significant cytotoxicity on MDR cells (SCG 7901/VCR) with only 8.75% of cells surviving.ConclusionMDR cancer therapy indicates that it may be important to develop a safer system that can simultaneously inhibit the drug transporters and monitor the delivery of chemotherapeutic agents, and combination therapy have raised widespread concern on tumor treatment.