Multidrug Resistance Phenomenon Research Articles

Snakes as sentinel of zoonotic yeasts and bio-indicators of environmental quality.

Reptiles in the wild or as pets may act as spreaders of bacteria, viruses, fungi and parasites. However, studies on the mycobiota of these animals are scanty. This study investigates the occurrence of yeasts from the cloacal swabs of snakes of different origins and the antifungal profile of the isolated strains. A total of 180 cloacal samples of snakes were collected from Morocco (Group I: n = 68) and Italy (Group II: n = 112). Yeast species were biochemically and molecularly identified. A total of 72 yeast strains belonging to 13 genera, 8 from snakes in Group I and five from snakes in Group II were identified. The most frequently isolated species were Trichosporon asahii (22.2%) and Candida tropicalis (15.3%) from snakes in Group I and Debaryomyces spp. (16.7%) and Metahyphopichia silvanorum (11.1%) from snakes in Group II. Multiple azole and amphotericin B (AmB) resistance phenomena were detected among isolated yeasts. Azole multi drug resistance phenomena were detected among yeasts from Group I and Rhodotorula mucilaginosa from Group II, whereas AmB resistance phenomena among those from Group II. Data suggest that snakes may harbor pathogenetic yeasts, being potential reservoirs and spreaders of these organisms in the environment. Since the yeast species community from different groups of animals as well as their antifungal profile reflects the epidemiology of human yeast infections in the same geographical areas, the results indicate that snakes may be considered as sentinels for human/animal pathogenic microorganisms and bio-indicators of environmental quality.

Usefulness of Natural Phenolic Compounds in the Fight against Esophageal Cancer: A Systematic Review

Esophageal cancer (EC) is a very common form of cancer in developing countries, and its exponential progression is a cause for concern. Available treatments face the phenomenon of multi-drug resistance, as well as multiple disabling side effects. The number of deaths is expected to double by 2030 if nothing is done. Due to their high representativeness in plants, phenolic compounds are a potential alternative for halting the spread of this disease, which bereaves many thousands of families every year. This study aims to identify phenolic compounds with activity against esophageal cancer, assess their toxicological profiles, and explore future perspectives. To achieve this, the literature search was meticulously carried out in the Google Scholar, Scopus, Web of Sciences, and Pub-Med/Medline databases, in accordance with the PRISMA 2020 guidelines. The results show that proanthocyanidin and curcumin represent promising therapeutic options, given their significant in vitro and in vivo activity, and their safety in human subjects in clinical trials. Moscatilin, Genistein, and pristimerin have anticancer activities (≤10 µM) very close to those of doxorubicin and 5-FU, although their safety has not yet been fully established. The compounds identified in vivo exhibit highly significant activities compared with the results obtained in vitro, and are sometimes more effective than the molecules conventionally used to treat EC. Generally, with the exceptions of plumbagin, lapachol, and β-lapachone, all other molecules are relatively non-toxic to normal human cells and represent a therapeutic avenue to be explored by pharmaceutical companies in the fight against esophageal cancer. However, more detailed toxicological studies of certain molecules remain a priority.

Effect of a phthalate derivative purified from Bacillus zhangzhouensis SK4 on quorum sensing regulated virulence factors of Pseudomonas aeruginosa

Pseudomonas aeruginosa causes life-threatening diseases and is resistant to almost all conventional antibiotics. The quorum sensing (QS) system of P. aeruginosa contributes to many pathogenic factors some of which are pigment production, motility, and biofilm. The disruption of quorum sensing system may be an impactful strategy to deal with infections. The present study investigates the anti-quorum sensing property of a bioactive molecule extracted from marine epibiotic bacteria present on the surface of seaweeds. Among all the isolates tested against monitor strain Chromobacterium violaceum (MTCC 2656), the one with the highest activity was identified as Bacillus zhangzhouensis SK4. The culture supernatant was extracted with chloroform which was then partially purified by TLC and column chromatography. The probable anti-QS compound was identified as 1,2-benzenedicarboxylic acid, bis (2-methylpropyl ester) by GC-MS and NMR analysis. The treatment of P. aeruginosa MCC 3457 with the lead compound resulted in the reduced production of pyocyanin, rhamnolipids, exopolysaccharide, biofilm, and motility. The observations of light and scanning electron microscopy also supported the biofilm inhibition. The lead compound showed synergism with the meropenem antibiotic and significantly reduced MIC. The molecular docking and pharmacokinetics study predicted 1, 2-benzenedicarboxylic acid, bis (2-methylpropyl ester), a phthalate derivative as a good drug candidate. The molecular dynamics study was also performed to check the stability of the lead compound and LasR complex. Further, lead compounds did not exhibit any cytotoxicity when tested on human embryonic kidney cells. As per our knowledge, this is the first report on the anti-QS activity of B. zhangzhouensis SK4, indicating that epibiotic bacteria can be a possible source of novel compounds to deal with the multidrug resistance phenomenon.

Investigating Drug Interactions And Antibacterial Activity Of Vitamin C On Pathogenic Factors Of Escherichia Coli Clinical Isolates

Today, the phenomenon of multi-drug resistance has become a major cause of concern, and insufficient achievements have been made in the development of new antibiotics for the treatment of bacterial infections. Therefore, there is an unmet need for new auxiliary search. Vitamin C is one such promising supplement. The current study was conducted with the aim of explaining the antibacterial interaction effect of vitamin C in different concentrations (5-20 mg/ml) and drugs effective on Escherichia coli bacteria. In order to collect clinical samples during the months of September to November 2022, clinical samples were collected from 100 patients suspected of urinary tract infection who referred to medical centers. For identification, biochemical tests and gram staining and culture in IMViC and EMB environments were used to see metallic green polish. Then antimicrobial sensitivity test And the effect of antibiotic on biofilm formation, the effect of antibiotic and ascorbic acid on biofilm formation, biofilm inhibition rate was done for the single and combined effects of both antimicrobial substances. Finally, in order to investigate and identify the virulence gene of the isolated strains, DNA extraction was performed by PCR method. 45 samples of urinary infection culture were identified from the total of 100 samples collected, in 45 (45%) of them colonies with metallic polish were observed. 45% were men and 55% were women, and of these, a total of 45 positive E. coli cases were found in women and 17 positive cases were seen in men. Less than one year, teenagers, young and old were divided. 2 cases (2%) were in the age group of less than one year, 3 cases (3%) were teenagers, 63 cases (63%) were young and 32 cases (32%) were in the age group of middle-aged people. In a situation where the ability to form biofilm under vitamin C (ascorbic acid) treatment was not very effective and did not differ much from normal conditions, antibiotic treatment (under MBC gentamicin treatment) was somewhat successful in inhibiting biofilm formation, finally with the combination of antibiotic and Ascorbic acid was completely isolated in many resistant strains, the inability to form biofilm was evident, and this indicated the synergistic effects in the investigated composition. As the results showed, the ability to produce biofilm in the samples that had the target genes in this study was not much different from the other samples. Considering the increasing resistance to some antibiotics and wide changes in the effective spectrum of drugs and preventing the increase of drug-resistant cases, the necessity of conducting drug sensitivity tests seems very necessary. The high prevalence of E. coli antibiotic resistance and the high percentage of resistance genes in patients suffering from infections caused by this bacterium can indicate the excessive use of antibiotics. Finally, the prevalence of antibiotic resistance is a useful marker for investigating resistance genes and can be useful in ecological investigations. Also, with clear inhibitory effects, the selected antibiotic in this study along with ascorbic acid, this vitamin can be used as a supplement in some infections caused by E. coli bacteria.

Importance of the Aspergillus fumigatus Mismatch Repair Protein Msh6 in Antifungal Resistance Development.

One of the systems responsible for the recognition and repair of mistakes occurring during cell replication is the DNA mismatch repair (MMR) system. Two major protein complexes constitute the MMR pathway: MutS and MutL. Here, we investigated the possible relation of four A. fumigatus MMR genes (msh2, msh6, pms1, and mlh1) with the development of azole resistance related to the phenomenon of multi-drug resistance. We examined the MMR gene variations in 163 Aspergillus fumigatus genomes. Our analysis showed that genes msh2, pms1, and mlh1 have low genetic variability and do not seem to correlate with drug resistance. In contrast, there is a nonsynonymous mutation (G240A) in the msh6 gene that is harbored by 42% of the strains, most of them also harboring the TR34/L98H azole resistance mechanism in cyp51A. The msh6 gene was deleted in the akuBKU80A. fumigatus strain, and the ∆msh6 isolates were analyzed for fitness, azole susceptibility, and virulence capacity, showing no differences compared with the akuBKU80 parental strain. Wild-type msh6 and Δmsh6 strains were grown on high concentrations of azole and other non-azole fungicides used in crop protection. A 10- and 2-fold higher mutation frequency in genes that confer resistance to boscalid and benomyl, respectively, were observed in Δmsh6 strains compared to the wild-type. This study suggests a link between Msh6 and fungicide resistance acquisition.

Footprints of Nanocarrier on multi drug resistance therapy

As it is commonly recognized, the phenomenon of multidrug resistance (MDR) is increasingly prevalent on a global scale, posing significant challenges in the realm of treatment. MDR refers to a condition where resistance to various medications, which may differ in their chemical composition and mode of action, arises due to the presence of numerous mechanisms. In response to multidrug resistance (MDR), developing technologies in the field of nanotechnology, particularly Nanocarrier, are being utilized as counteractive measures. Nanocarrier refers to biodegradable materials that are employed in the field of drug delivery. Their primary function is to improve the solubility of medications that have low solubility, boosting their bioavailability. Additionally, nanocarriers enable the timed release of drugs and facilitate the accurate targeting of specific areas inside the body. Nanocarriers exhibit a diverse range of morphologies and dimensions, encompassing nanofibers, nanocomposites, nanoparticles, and nanotubes. These nanocarriers can be administered through injection, subcutaneous delivery, or intramuscular administration. In this review article, we focus on different nanocarriers and their use in MDR.

Succinct review on emergent crisis of antibiotics resistant (MDR) bacteria: impact on human health worldwide

Multidrug resistance (MDR) has become an alarming global health menace due to either overuse or abuse of antibiotics. It has happened because of lack of proper diagnostic testing and absence of general medical awareness including overuse of antibiotics in livestock and animal husbandry. Indeed, increased MDR phenomenon is led to increase in global mortality and morbidity because of diseases treatment failures that impacted global healthcare costs. It is done due to inappropriate continual use of antibiotics in human therapies, in animal husbandry and aquaculture farming practices that resulted in increase the incidence of pathogenic bacteria becoming resistant to multiple drugs. Multidrug resistant (MDR) bacteria are very common to become prevalent causes of community-acquired infections that associated with increased morbidity, mortality and healthcare costs. Colonisation of foreign patients by MDR bacteria is found to major health concern as predisposing factors in hospitals. During hospitalization and ICU treatment of critically ill foreign patients including travellers/tourists are found to having increased risk of acquiring MDR bacteria when hospitalized abroad. Hence, all these multiple factors led to fuelling in antibiotic resistance of bacteria during pandemic crisis and causing lethal effect in cancer patients due to treatment. Antibiotic resistant pathogens to protect world human population from this global health threat. So, this stipulated review is highlighted the insight of various notable aspects of fuelling of antibiotic resistance in bacteria including their possible modes of actions and ingrained impacts on human health. Henceforth, it is the peak era to explore new sustainable therapeutic alternatives to curb increase in global MDR crisis.

Antimicrobial resistance in food-associated Escherichia coli in Mexico and Latin America.

The World Health Organization (WHO) considers antimicrobial resistance to be one of the critical global public health priorities to address. Escherichia coli is a commensal bacterium of the gut microbiota in humans and animals; however, some strains cause infections and are resistant to antibiotics. One of the most common ways of acquiring pathogenic E. coli strains is through food. This review analyzes multidrug-resistant E. coli isolated from food, emphasizing Latin America and Mexico, and the mobile genetic elements (MGEs) responsible for spreading antibiotic resistance determinants among bacteria in different environments and hosts. We conducted a systematic search of the literature published from 2015 to 2022 in open access databases and electronic repositories. The prevalence of 11 E. coli pathotypes was described, with diarrheagenic E. coli pathotypes being the most frequently associated with foodborne illness in different Latin American countries, highlighting the presence of different antibiotic resistance genes mostly carried by IncF-type plasmids or class 1 integrons. Although the global incidence of foodborne illness is high, there have been few studies in Mexico and Latin America, which highlights the need to generate updated epidemiological data from the "One Health" approach, which allows monitoring of the multidrug-resistance phenomenon in E. coli from a common perspective in the interaction of human, veterinary, and environmental health.

Exploring the Functional Significance of Lysosomes in Cancer Drug Resistance

Chemotherapy stands as a primary therapeutic approach for tackling a spectrum of malignancies. Nonetheless, the emergence of resistance to chemotherapeutic agents poses a significant hurdle in achieving curative cancer treatments. Lysosomes, recognized as acidic cellular organelles predominantly engaged in intracellular digestion, have garnered increasing attention due to their implications in cancer biology. Notably, their relevance to cancer manifests in several ways: Firstly, the extracellular release of lysosomal enzymes actively promotes tumorigenesis. Secondly, the leakage of lysosomal hydrolases into the cytosol induces apoptosis. Lastly, weak chemotherapeutic bases, upon traversing the lysosomal membrane, become sequestered within lysosomes while adopting a cationic state. This sequestration of drugs within lysosomes diminishes their cytotoxic potential, restricts their availability at target sites, and contributes significantly to the development of drug resistance in cancer. This review comprehensively explores diverse mechanisms underpinning lysosomal drug sequestration and delves into their repercussions on the phenomenon of multidrug resistance in cancer. Furthermore, we delve into strategies aimed at surmounting drug resistance by leveraging lysosomes as subcellular targets, with the aim of reversing drug sequestration and thwarting drug resistance in the context of cancer therapy

Therapeutic Potential of 1,8-Dihydroanthraquinone Derivatives for Breast Cancer.

Breast cancer (BC) is the most common malignancy among women worldwide. In recent years, significant progress has been made in BC therapy. However, serious side effects resulting from the use of standard chemotherapeutic drugs, as well as the phenomenon of multidrug resistance (MDR), limit the effectiveness of approved therapies. Advanced research in the BC area is necessary to create more effective and safer forms of therapy to improve the outlook for individuals diagnosed with this aggressive neoplasm. For decades, plants and natural products with anticancer properties have been successfully utilized in treating various medical conditions. Anthraquinone derivatives are tricyclic secondary metabolites of natural origin that have been identified in plants, lichens, and fungi. They represent a few botanical families, e.g., Rhamnaceae, Rubiaceae, Fabaceae, Polygonaceae, and others. The review comprehensively covers and analyzes the most recent advances in the anticancer activity of 1,8-dihydroanthraquinone derivatives (emodin, aloe-emodin, hypericin, chrysophanol, rhein, and physcion) applied both individually, or in combination with other chemotherapeutic agents, in in vitro and in vivo BC models. The application of nanoparticles for in vitro and in vivo evidence in the context of 1,8-dihydroanthraquinone derivatives was also described.

Exploring and targeting potential druggable antimicrobial resistance targets ArgS, SecY, and MurA in Staphylococcus sciuri with TCM inhibitors through a subtractive genomics strategy.

Staphylococcus sciuri (also currently Mammaliicoccus sciuri) are anaerobic facultative and non-motile bacteria that cause significant human pathogenesis such as endocarditis, wound infections, peritonitis, UTI, and septic shock. Methicillin-resistant S. sciuri (MRSS) strains also infects animals that include healthy broilers, cattle, dogs, and pigs. The emergence of MRSS strains thereby poses a serious health threat and thrives the scientific community towards novel treatment options. Herein, we investigated the druggable genome of S. sciuri by employing subtractive genomics that resulted in seven genes/proteins where only three of them were predicted as final targets. Further mining the literature showed that the ArgS (WP_058610923), SecY (WP_058611897), and MurA (WP_058612677) are involved in the multi-drug resistance phenomenon. After constructing and verifying the 3D protein homology models, a screening process was carried out using a library of Traditional Chinese Medicine compounds (consisting of 36,043 compounds). The molecular docking and simulation studies revealed the physicochemical stability parameters of the docked TCM inhibitors in the druggable cavities of each protein target by identifying their druggability potential and maximum hydrogen bonding interactions. The simulated receptor-ligand complexes showed the conformational changes and stability index of the secondary structure elements. The root mean square deviation (RMSD) graph showed fluctuations due to structural changes in the helix-coil-helix and beta-turn-beta changes at specific points where the pattern of the RMSD and root mean square fluctuation (RMSF) (< 1.0Å) support any major domain shifts within the structural framework of the protein-ligand complex and placement of ligand was well complemented within the binding site. The β-factor values demonstrated instability at few points while the radius of gyration for structural compactness as a time function for the 100-ns simulation of protein-ligand complexes showed favorable average values and denoted the stability of all complexes. It is assumed that such findings might facilitate researchers to robustly discover and develop effective therapeutics against S. sciuri alongside other enteric infections.

Curcuminoids as Anticancer Drugs: Pleiotropic Effects, Potential for Metabolic Reprogramming and Prospects for the Future.

The number of published studies on curcuminoids in cancer research, including its lead molecule curcumin and synthetic analogs, has been increasing substantially during the past two decades. Insights on the diversity of inhibitory effects they have produced on a multitude of pathways involved in carcinogenesis and tumor progression have been provided. As this wealth of data was obtained in settings of various experimental and clinical data, this review first aimed at presenting a chronology of discoveries and an update on their complex in vivo effects. Secondly, there are many interesting questions linked to their pleiotropic effects. One of them, a growing research topic, relates to their ability to modulate metabolic reprogramming. This review will also cover the use of curcuminoids as chemosensitizing molecules that can be combined with several anticancer drugs to reverse the phenomenon of multidrug resistance. Finally, current investigations in these three complementary research fields raise several important questions that will be put among the prospects for the future research related to the importance of these molecules in cancer research.

Bacterial Zinc Metalloenzyme Inhibitors: Recent Advances and Future Perspectives.

Human deaths caused by Gram-negative bacteria keep rising due to the multidrug resistance (MDR) phenomenon. Therefore, it is a priority to develop novel antibiotics with different mechanisms of action. Several bacterial zinc metalloenzymes are becoming attractive targets since they do not show any similarities with the human endogenous zinc-metalloproteinases. In the last decades, there has been an increasing interest from both industry and academia in developing new inhibitors against those enzymes involved in lipid A biosynthesis, and bacteria nutrition and sporulation, e.g., UDP-[3-O-(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC), thermolysin (TLN), and pseudolysin (PLN). Nevertheless, targeting these bacterial enzymes is harder than expected and the lack of good clinical candidates suggests that more effort is needed. This review gives an overview of bacterial zinc metalloenzyme inhibitors that have been synthesized so far, highlighting the structural features essential for inhibitory activity and the structure-activity relationships. Our discussion may stimulate and help further studies on bacterial zinc metalloenzyme inhibitors as possible novel antibacterial drugs.

Expression of GnT-III decreases chemoresistance via negatively regulating P-glycoprotein expression: Involvement of the TNFR2-NF-κB signaling pathway

The phenomenon of multidrug resistance (MDR) is called chemoresistance with respect to the treatment of cancer, and it continues to be a major challenge. The role of N-glycosylation in chemoresistance, however, remains poorly understood. Here, we established a traditional model for adriamycin resistance in K562cells, which are also known as K562/adriamycin-resistant (ADR) cells. Lectin blot, mass spectrometry, and RT-PCR analysis showed that the expression levels of N-acetylglucosaminyltransferase III (GnT-III) mRNA and its products, bisected N-glycans, are significantly decreased in K562/ADR cells, compared with the levels in parent K562cells. By contrast, the expression levels of both P-glycoprotein (P-gp) and its intracellular key regulator, NF-κB signaling, are significantly increased in K562/ADR cells. These upregulations were sufficiently suppressed by the overexpression of GnT-III in K562/ADR cells. We found that the expression of GnT-III consistently decreased chemoresistance for doxorubicin and dasatinib, as well as activation of the NF-κB pathway by tumor necrosis factor (TNF) α, which binds to two structurally distinct glycoproteins, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), on the cell surface. Interestingly, our immunoprecipitation analysis revealed that only TNFR2, but not TNFR1, contains bisected N-glycans. The lack of GnT-III strongly induced TNFR2's autotrimerization without ligand stimulation, which was rescued by the overexpression of GnT-III in K562/ADR cells. Furthermore, the deficiency of TNFR2 suppressed P-gp expression while it increased GnT-III expression. Taken together, these results clearly show that GnT-III negatively regulates chemoresistance via the suppression of P-gp expression, which is regulated by the TNFR2-NF/κB signaling pathway.

Anti-drug resistance, anti-inflammation, and anti-proliferation activities mediated by melatonin in doxorubicin-resistant hepatocellular carcinoma: in vitro investigations

Hepatocellular carcinoma (HCC) is the major life-threatening primary liver malignancy in both sexes all over the world. Unfortunately, the majority of patients are diagnosed at later stages because HCC does not elicit obvious symptoms during its early incidence. Consequently, most individuals escape the first-line HCC treatments and are treated with chemotherapy. Regrettably, the therapeutic outcomes for those patients are usually poor because of the development of multidrug resistance phenomena. Furthermore, most anti-HCC therapies cause severe undesired side effects that notably interfere with the life quality of such patients. Accordingly, there is an important need to search for an alternative therapeutic drug or adjuvant which is more efficient with safe or even minimal side effects for HCC treatment. Melatonin was recently reported to exert intrinsic antitumor activity in different cancers. However, the regulatory pathways underlying the antitumor activity of melatonin are poorly understood in resistant liver cells. Furthermore, a limited number of studies have addressed the therapeutic role of melatonin in HCC cells resistant to doxorubicin chemotherapy. In this study, we investigated the antitumor effects of melatonin in doxorubicin-resistant HepG2 cells and explored the regulatory pivotal targets underlying these effects. To achieve our aim, an MTT assay was used to calculate the 50% inhibitory concentration of melatonin and evaluate its antiproliferative effect on resistant cells. Additionally, qRT-PCR was used to quantify genes having a role in drug resistance phenotype (ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2); apoptosis (caspases-3, and -7, Bcl2, Bax, and p53); anti-oxidation (NRF2); expression of melatonin receptors (MT1, MT2, and MT3); besides, programmed death receptor PD-1 gene. The active form of the caspase-3 enzyme was estimated by ELISA. A human inflammatory antibody membrane array was employed to quantify forty inflammatory factors expressed in treated cells. We observed that melatonin inhibited the proliferation of doxorubicin-resistant HepG2 cells in a dose-dependent manner after 24-h incubation time with a calculated IC50 greater than 10 mM (13.4 mM), the expression levels of genes involved in drug resistance response (ABCB1, ABCC1, ABCC5, and ABCG2) were downregulated. Also, the expression of caspase-3, Caspase-7, NRF2, and p53 genes were expressed at higher levels as compared to control (DMSO-treated cells). An active form of caspase-3 was confirmed by ELISA. Moreover, the anti-inflammatory effect of melatonin was detected through the calculated fold change to control which was reduced for various mediators that have a role in the inflammation pathway. The current findings introduce melatonin as a promising anti-cancer treatment for human-resistant HCC which could be used in combination with current chemotherapeutic regimens to improve the outcome and reduce the developed multidrug resistance.

A New ABCB1 Inhibitor Enhances the Anticancer Effect of Doxorubicin in Both In Vitro and In Vivo Models of NSCLC.

In tumors, the multi drug resistance phenomenon may occur through the efflux of chemotherapeutic drugs out of cancer cells, impeding their accumulation, and eventually reducing their toxicity. This process is mediated by transporters overexpressed in the plasma membranes of tumor cells, among which is the P-glycoprotein/multidrug resistance 1/ATP-binding cassette B1 (P-gp/MDR1/ABCB1). The aim of this study was to explore the effect of a new molecule, called AIF-1, on ABCB1 activity. In a cellular model of non-small cell lung cancer (NSCLC), AIF-1 significantly inhibited ABCB1 activity, which was evaluated by the fluorimetric measurement of the intracellular accumulation of calcein. AIF-1 also significantly increased the intracellular content of doxorubicin, which was evaluated by confocal microscopy and LC-MS/MS analysis. This effect translated to higher cytotoxicity of doxorubicin and reduced cellular proliferation. Finally, in a murine xenograft model, the tumor volume increased by 267% and 148% on average in mice treated with vehicle and doxorubicin alone, respectively. After the co-administration of doxorubicin with AIF-1, tumor volume increased by only 13.4%. In conclusion, these results suggest enhancement of the efficacy of the chemotherapeutic drug doxorubicin by AIF-1, laying the basis for the future development of new ABCB1 inhibitors for tumor treatment.

Evaluation of Drug Resistance in the Tamoxifen-treated MKN-45 Gastric Cancer Cell Line via the Epithelial-mesenchymal Transition Signaling Pathway.

One of the major challenges in gastric cancer (GC) chemotherapy is the phenomenon of multi-drug resistance (MDR). The epithelial-mesenchymal transition (EMT) and its key molecules, transforming growth factor-β (TGFβ) and SMAD2, play a central role in MDR occurrence. Tamoxifen (TAM), a triphenylethylene derivative, can overcome MDR in human gastric cancers. The aim of this study was to investigate the effect of TAM on 5-FU resistance of GC by suppressing the TGFβ1/SMAD2 signaling pathway and EMT. The MKN-45 cell line was subjected to treatment with 5-FU, TAM and a combination of both. The MTT assay was used to investigate the cytotoxic effects of 5-FU and TAM, and the DNA laddering technique was used to assess DNA fragmentation and apoptosis. Real-time RT-PCR examined the change in gene expression in EMT-related genes (SNAI2, VIM, TGFβ1 and SMAD2). The results of the present study indicated that not only TAM treatment significantly decreased the IC50 of 5-FU (P≤0.05), but also the addition of TAM to 5-FU induced apoptosis in the MKN-45 cell line. Treatment with TAM and 5-FU significantly inhibited TGFβ1 and TGFβ1-induced expression of EMT markers (VIM and SNAI2) in MKN-45 cells (P≤0.05). The reduction of TGFβ1 targets downstream of the SMAD2 signaling pathway reversed the process of EMT and significantly increased the sensitivity of MKN-45 cells to 5-FU. The results of the present study suggested that reversal of EMT-mediated MDR via the TGFβ1/SMAD signaling pathway using TAM may be a potential new therapeutic strategy to overcome chemoresistance to 5-FU during GC chemotherapy.

Evaluation of antibacterial activity of vitamin C against human bacterial pathogens.

Now a day's multidrug resistance phenomenon has become the main cause for concern and there has been an inadequate achievement in the development of novel antibiotics to treat the bacterial infections. Therefore, there is an unmet need to search for novel adjuvant. Vitamin C is one such promising adjuvant. The present study was aimed to elucidate the antibacterial effect of vitamin C at various temperatures (4°C, 37°C and 50°C) and pH (3, 8, and 11), against Gram-positive and Gram-negative bacteria at various concentrations (5-20 mg/ml) through agar well diffusion method. Growth inhibition of all bacterial strains by vitamin C was concentration-dependent. Vitamin C significantly inhibited the growth of Gram-positive bacteria: Bacillus licheniformis (25.3 ± 0.9 mm), Staphylococcus aureus (22.0 ± 0.6 mm), Bacillus subtilis (19.3 ± 0.3 mm) and Gram-negative bacteria: Proteus mirabilis (27.67 ± 0.882 mm), Klebsiella pneumoniae (21.33±0.9 mm), Pseudomonas aeruginosa (18.0 ± 1.5 mm) and Escherichia coli (18.3 ± 0.3 mm). The stability of vitamin C was observed at various pH values and various temperatures. Vitamin C showed significant antibacterial activity at acidic pH against all bacterial strains. Vitamin C remained the stable at different temperatures. It was concluded that vitamin C is an effective and safe antibacterial agent that can be used in the future as an adjunct treatment option to combat infections in humans.

Detection of Bacteria Causing Skin Infections in Mosul City and Studying its Resistance to Antibiotics

The current study was conducted to detect the bacteria that causes skin infections in Mosul city and to study its resistance pattern to different antibiotics. For this purpose, 30 swab samples were collected from different skin infections from patients referred to the dermatology consultations of Al-Salam Teaching Hospital and Mosul GeneralHospital in Mosul city. The results of isolation and diagnosis showed that (20) samples, 66.6% of the total samples were positive for bacterial culture. (56.5%) of isolated bacteria were Gram-negative and 43.5% belonged to Gram-positive bacteria. The isolation percentage for Staphylococcus aureus and Sphingomonas paucimobillis were (17.3%) each, Pantoea spp. (13%), and all three species belonging to the genus Kocuria and Klebsiella pneumonia was 8.6% each, while Acinetobacter baumannii , Brevundimonas diminuta, Enterobacter aerogenes, and Pseudomonas luteola were isolated by (4.3%) each. The results for antibiotic sensitivity showed the prevalence of multidrug resistance (MDR) phenomenon in all isolates, and the isolates showed a clear variation in their resistance to each antibiotic. The highest percentage of resistance towards antibiotics were (69.5%) and (60.8%) against the Oxacillin and Penicillin, respectively. All isolates were sensitive towards levofloxacin, which makes it a suitable treatment option for infections associated with the bacteria understudy.

Recent Advances on P-Glycoprotein (ABCB1) Transporter Modelling with In Silico Methods

ABC transporters play a critical role in both drug bioavailability and toxicity, and with the discovery of the P-glycoprotein (P-gp), this became even more evident, as it plays an important role in preventing intracellular accumulation of toxic compounds. Over the past 30 years, intensive studies have been conducted to find new therapeutic molecules to reverse the phenomenon of multidrug resistance (MDR) ), that research has found is often associated with overexpression of P-gp, the most extensively studied drug efflux transporter; in MDR, therapeutic drugs are prevented from reaching their targets due to active efflux from the cell. The development of P-gp inhibitors is recognized as a good way to reverse this type of MDR, which has been the subject of extensive studies over the past few decades. Despite the progress made, no effective P-gp inhibitors to reverse multidrug resistance are yet on the market, mainly because of their toxic effects. Computational studies can accelerate this process, and in silico models such as QSAR models that predict the activity of compounds associated with P-gp (or analogous transporters) are of great value in the early stages of drug development, along with molecular modelling methods, which provide a way to explain how these molecules interact with the ABC transporter. This review highlights recent advances in computational P-gp research, spanning the last five years to 2022. Particular attention is given to the use of machine-learning approaches, drug-transporter interactions, and recent discoveries of potential P-gp inhibitors that could act as modulators of multidrug resistance.