Development Of Resistance Research Articles

Tumor Heterogeneity Shapes Survival Dynamics in Drug-Treated Cells, Revealing Size-Drifting Subpopulations.

The goal of this project was to demonstrate that subpopulations of cells in tumors can uniquely fluctuate in size in response to environmental conditions created during drug treatment, thereby acting as a dynamic "rheostat" to create a favorable tumor environment for growth. The cancer modeling used for these studies was subpopulations of melanoma cells existing in cultured and tumor systems that differed in aldehyde dehydrogenase (ALDH) activity. However, similar observations were found in other cancer types in addition to melanoma, making them applicable broadly across cancer. The approach was designed to show that either ALDHhigh and ALDHlow subpopulations rapidly epigenetically transition between stem-cell-like high into nonstem-like low production states to create an environment during drug treatment that would enable optimal cellular proliferation and tumor expansion to facilitate drug resistance. The controlled experiments showed proportional changes in each cell population to reach an evolutionarily stable equilibrium mediated by the needed levels of ALDH enzyme activity. Mechanistically, cell population size changes served to functionally move the aldehyde and the resulting reactive oxygen species (ROS) levels to those compatible with optimal cellular proliferation with population fluctuations dependent on the levels of drug induced tumor stress. This is the first report documenting fluctuations in the sizes of cell populations in tumors to cooperatively assist in drug resistance development.

Chemical Composition and Insecticidal Potential of Essential Oil from Murraya koenigii (L.) Obtained by Natural Deep Eutectic Solvents.

Aphis craccivora Koch and Planococcus lilacinus Cockerell are phloem feeders and act as vectors for transmitting plant viruses to agricultural and horticultural crops thereby damaging them. The persistent and widespread use of synthetic, wide-spectrum pesticides has resulted in resistance development that is detrimental to the environment, human health, and natural enemies of pests. The present investigation uses various extraction mediums to examine the insecticidal efficacy of essential oils (EOs) isolated from Murraya koenigii (L.) leaves. Increase in yield was observed in the EO extracted using NADES-AHD [0.16% (obtained with hydro-distillation)] to 0.30% [obtained with N-1 (glycerol:lactic acid)]. EO obtained with water was found more effective against A. craccivora (LD50 = 0.89 µL/insect) and followed by N-1 (glycerol:lactic acid), and N-3 (choline chloride:citric acid) (LD50 = 1.29-1.38 µL/insect). Similarly, EO isolated by water and N-4 (choline chloride:oxalic acid) was effective against P. lilacinus (LD50 = 2.63-3.06 µL/insect). Additionally, the EO prepared by water substantially reduced glutathione S-transferase (GST) and acetylcholinesterase (AChE) in target pests, suggesting that these enzymes may be the EOs' site of action. NADES-AHD has enhanced the EO yield as compared to the conventional method. The EO obtained with water showed promising toxicity against target pests and target site of action. Therefore, based on field and greenhouse bio-efficacy experiments, EOs/biopesticides/botanicals can be proposed for controlling the spread of mealy bugs and aphids.

Pathogen-encoded Rum DNA polymerase drives rapid bacterial drug resistance.

The acquisition of multidrug resistance by pathogenic bacteria is a potentially incipient pandemic. Horizontal transfer of DNA from mobile integrative conjugative elements (ICEs) provides an important way to introduce genes that confer antibiotic (Ab)-resistance in recipient cells. Sizable numbers of SXT/R391 ICEs encode a hypermutagenic Rum DNA polymerase (Rum pol), which has significant homology with Escherichia coli pol V. Here, we show that even under tight transcriptional and post-transcriptional regulation imposed by host bacteria and the R391 ICE itself, Rum pol rapidly accelerates development of multidrug resistance (CIPR, RifR, AmpR) in E. coli in response to SOS-inducing Ab and non-Ab external stressors bleomycin (BLM), ciprofloxacin (CIP) and UV radiation. The impact of Rum pol on the rate of acquisition of drug resistance appears to surpass potential contributions from other cellular processes. We have shown that RecA protein plays a central role in controlling the ability of Rum pol to accelerate antibiotic resistance. A single amino acid substitution in RecA, M197D, acts as a 'Master Regulator' that effectively eliminates the Rum pol-induced Ab resistance. We suggest that Rum pol should be considered as one of the major factors driving development of de novo Ab resistance in pathogens carrying SXT/R391 ICEs.

The EP3-ZNF488 Axis Promotes Self-Renewal of Glioma Stem-like Cells to Induce Resistance to Tumor Treating Fields.

Tumor Treating Fields (TTFields) employ low-intensity, alternating electric fields to exert antitumor activity and have demonstrated efficacy against multiple cancers, including glioblastoma (GBM). Unfortunately, cancer cells inevitably develop resistance to TTFields, highlighting the need to elucidate the underlying mechanisms to develop approaches to induce durable responses. Using a gene network-based machine-learning algorithm, we interrogated TTFields-resistant GBM cells and uncovered a regulatory axis anchored by the prostaglandin E receptor 3 (EP3) and the transcription factor zinc finger 488 (ZNF488). Mechanistically, TTFields induced EP3 upregulation and nuclear envelope localization, where it formed a complex with ZNF488 to induce resistance to TTFields by promoting self-renewal of glioma stem-like cells (GSC). Overexpression of EP3 and/or ZNF488 in TTFields-sensitive GSC conferred resistance and enhanced self-renewal, while expression of non-interacting mutants of these proteins abrogated formation of the nuclear complex and prevented resistance. Inhibition of either partner in this protein complex in resistant GSC, including those freshly isolated from TTFields-resistant GBM tumors, re-sensitized cells to the cytotoxic effects of TTFields, concomitant with reduced self-renewal and in vivo tumorigenicity. Importantly, inhibition of EP3 in TTFields-sensitive GSC preemptively halted the development of resistance. The EP3-ZNF488 axis was significantly upregulated in TTFields-resistant GBM tumors, and co-expression of EP3 and ZNF488 in other cancers correlated with lower survival rates. Collectively, these results indicate that the nuclear EP3-ZNF488 axis is necessary and sufficient to establish TTFields resistance, underscoring the potential to target this axis to prevent or reverse resistance in GBM and possibly other cancers.

Development of Low-Toxicity Antimicrobial Polycarbonates Bearing Lysine Residues.

Antibiotic resistance has been threatening public health for a long period, while the COVID pandemic aggravated the scenario. To combat antibiotic resistance strains, host defense peptides (HDPs) mimicking molecules have attracted considerable attention. Herein, we reported a series of polycarbonates bearing cationic lysine amino acid residues that could mimic the mechanism of action of HDPs and possess broad-spectrum antimicrobial activity. Moreover, those polymers had negligible toxicity toward red blood cells and mammalian cells. The membrane-disruption mechanism endows the lysine-containing polycarbonates with low possibility of resistance development and the fast killing kinetics, making them promising candidates for antimicrobial development.

Overexpression of l,d-Transpeptidase A Induces Dispensability of Rod Complex in Escherichia coli.

Antimicrobial resistance (AMR) is a significant global threat, and the presence of resistance-determinant genes is one of the major driving forces behind it. The bacterial rod complex is an essential set of proteins that is crucial for cell survival due to its role in cell wall biogenesis and shape maintenance. Therefore, these proteins offer excellent potential as drug targets; however, compensatory mutations in nontarget genes render this complex nonessential. The MreB protein of this complex is an actin homologue that rotates along the longitudinal axis of the cell to provide rod shape to the bacteria. In this study, using chemical-chemical interaction profiling and FtsZ suppression assay, we identified the MreB targeting activity of IITR07865, a previously discovered small molecule in our lab. Escherichia coli suppressors against IITR07865 revealed mutations in two cell division-associated genes, min C and pal, that have not been previously implicated in rod complex essentiality. IITR07865 resistant mutants were found to inactivate and render the rod complex nonessential, making the rod complex inhibitors ineffective. Further, through transcriptome analysis, we reveal the primary cause of resistance in suppressor strains to be the overexpression of an l, d-transpeptidase A enzyme, which is involved in peptidoglycan and Braun's lipoprotein cross-linking. Our results demonstrate a novel mechanism of resistance development in rod-shaped Gram-negative bacterial pathogen E. coli involved in UTIs where mecillinam, a clinically used antibiotic that targets rod complex, is a drug of choice.

Artemisinin-resistant malaria.

SUMMARYThe artemisinin antimalarials are the cornerstone of current malaria treatment. The development of artemisinin resistance in Plasmodium falciparum poses a major threat to malaria control and elimination. Recognized first in the Greater Mekong subregion of Southeast Asia nearly 20 years ago, artemisinin resistance has now been documented in Guyana, South America, in Papua New Guinea, and most recently, it has emerged de novo in East Africa (Rwanda, Uganda, South Sudan, Tanzania, Ethiopia, Eritrea, and eastern DRC) where it has now become firmly established. Artemisinin resistance is associated with mutations in the propeller region of the PfKelch gene, which play a causal role, although the parasites' genetic background also makes an important contribution to the phenotype. Clinically, artemisinin resistance manifests as reduced parasiticidal activity and slower parasite clearance and thus an increased risk of treatment failure following artemisinin-based combination therapy (ACT). This results from the loss of artemisinin activity against the younger circulating ring stage parasites. This loss of activity is likely to diminish the life-saving advantage of artesunate in the treatment of severe falciparum malaria. Gametocytocidal and thus transmission blocking activities are also reduced. At current levels of resistance, artemisinin-resistant parasites still remain susceptible at the trophozoite stage of asexual development, and so, artemisinin still contributes to the therapeutic response. As ACTs are the most widely used antimalarial drugs in the world, it is essential from a malaria control perspective that ACT cure rates remain high. Better methods of identifying uncomplicated hyperparasitemia, the main cause of ACT treatment failure, are required so that longer courses of treatment can be given to these high-risk patients. Reducing the use of artemisinin monotherapies will reduce the continued selection pressure which could lead potentially to higher levels of artemisinin resistance. Triple artemisinin combination therapies should be deployed as soon as possible to protect the ACT partner drugs and thereby delay the emergence of higher levels of resistance. As new affordable antimalarial drugs are still several years away, the control of artemisinin resistance must depend on the better use of available tools.

Development of drug resistance in cancer cells

Abstract Introduction/Objective The purpose of this study was to evaluate omeprazole treament in cancer cells. Methods/Case Report The colorectal cancer cell line, CACO2, was treated with omeprazole at two different concentrations and methotrexate as a positive control for 3-4 months. Using exon-spanning primers for the ABCG2 and ABCB1 genes, qPCR was used to monitor changes in mRNA expression of the efflux pumps, Breast Cancer Resistant Protein (BCRP) and P-glycoprotein (Pgp). Upregulation of BCRP and Pgp was observed through the western blot assay. Once overexpression of BCRP was confirmed, the omeprazole-treated and methotrexate-treated cells were tested for chemotherapy-resistance using the Prestoblue proliferation assay and were compared to the untreated cells. The omeprazole treatments were repeated for reproducibility using two esophageal cancer cell lines. The treated cells were also studied for expression changes of possible drug resistant and cancer genes using RNASeq analysis. Results (if a Case Study enter NA) N/A Conclusion Esophageal cancer patients, who are treated for acid reflux, may be at higher risk for developing chemotherapy-resistant/multidrug resistance (MDR) tumor cells prior to chemotherapy treatment. Esophageal cancer patients with MDR tumors will have lower chance of survival compared to patients who are responsive to chemotherapy treatment. By identifying the overexpression of BCRP in the tumor cells of cancer, oncologists will be able to use a better treatment plan with more effective chemotherapy drugs.

Advances in the role of membrane-bound transcription factors in carcinogenesis and therapy.

Protein shuttling between the cytoplasm and nucleus is a unique phenomenon in eukaryotic organisms, integral to various cellular functions. Membrane-bound transcription factors (MTFs), a specialized class of nucleocytoplasmic shuttling proteins, are anchored to the cell membrane and enter the nucleus upon ligand binding to exert their transcriptional regulatory functions. MTFs are crucial in cellular signal transduction, and aberrant nucleocytoplasmic shuttling of MTFs is closely associated with tumor initiation, progression, and resistance to anticancer therapies. Studies have demonstrated that MTFs, such as human epidermal growth factor receptor (HER), fibroblast growth factor receptor (FGFR), β-catenin, Notch, insulin-like growth factor 1 receptor (IGF-1R), and insulin receptor (IR), play critical roles in tumorigenesis and cancer progression. Targeted therapies developed against HERs and FGFRs, among these MTFs, have yielded significant success in cancer treatment. However, the development of drug resistance remains a major challenge. As research on MTFs progress, it is anticipated that additional MTF-targeted therapies will be developed to enhance cancer treatment. In this review, we summarized recent advancements in the study of MTFs and their roles in carcinogenesis and therapy, aiming to provide valuable insights into the potential of targeting MTF pathways for the reseach of therapeutic strategies.

Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice.

Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared to lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of metabolically associated steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health, and its loss predisposes mice to metabolically associated steatohepatitis.

Tetranychus urticae Koch Biology on Apple Trees

The two-spotted spider mite (Tetranychus urticae Koch) is a polyphagous arthropod herbivore that consumes over 1,100 plant species from 140 distinct plant families, including those producing harmful chemicals in temperate and tropical climates. It is an important pest in greenhouse and field cultivation, causing damage to various crops such as citrus, apples, grapes, tomatoes, peppers, cucumbers, strawberries, maize, and soy. T. urticae ability to spread over agricultural fields and adapt to environmental stressors is linked to its high propensity for mutation, leading to the highest frequency of pesticide resistance among arthropods. The genetic diversity of T. urticae gathered from apple orchards throughout Poland has been studied to investigate potential correlations between molecular variations and the occurrence of resistance to METI-acaricides. Research has shown that an abundance of leaf pubescence on the abaxial leaf surface adversely affects the development of European red mite, two-spotted spider mite, and carmine spider mite. However, due to variations in leaf sizes, tree canopy, tree ages, and the existence of natural enemies, it is impossible to compare data gathered due to variations in leaf sizes, tree canopy, tree ages, and the presence of natural enemies. Pesticide treatments negatively impact fruit plantations' ecosystems, devastating biodiversity, altering the makeup and structure of arthropod populations, and promoting mass reproduction of phytophage mites by displacing certain species with others. The most extensive research has been done on the common spider mite's development of resistance to avermectin group preparations, with some studies showing resistance to multiple acaricides.

Guanethidine Restores Tetracycline Sensitivity in Multidrug-Resistant Escherichia coli Carrying tetA Gene.

The worrying issue of antibiotic resistance in pathogenic bacteria is aggravated by the scarcity of novel therapeutic agents. Antibiotic adjuvants offer a promising solution due to their cost-effectiveness and high efficacy in addressing this issue, such as the β-lactamase inhibitor sulbactam (a β-lactam adjuvant) and the dihydrofolate reductase inhibitor trimethoprim (a sulfonamide adjuvant). This study aimed to discover potential adjuvants for tetracyclines from a list of previously approved drugs to restore susceptibility to Escherichia coli carrying the tetA gene. We have screened guanethidine, a compound from the Chinese pharmacopoeia, which effectively potentiates the activity of tetracyclines by reversing resistance in tetA-positive Escherichia coli, enhancing its antibacterial potency, and retarding the development of resistance. Guanethidine functions via the inhibition of the TetA efflux pump, thereby increasing the intracellular concentration of tetracyclines. Our findings suggest that guanethidine holds promise as an antibiotic adjuvant.

Amphiregulin Upregulation in Visfatin-Stimulated Colorectal Cancer Cells Reduces Sensitivity to 5-Fluororacil Cytotoxicity.

Colorectal cancer (CRC) has become a prevalent and deadly malignancy over the years. Drug resistance remains a major challenge in CRC treatment, significantly affecting patient survival rates. Obesity is a key risk factor for CRC development, and accumulating evidence indicates that increased secretion of adipokines, including Visfatin, under obese conditions contributes to the development of resistance in CRC to various therapeutic methods. Amphiregulin (AREG) is a member of the epidermal growth factor (EGF) family, which activates the EGF receptor (EGFR), influencing multiple tumorigenic characteristics of cancers. Abnormal expression levels of AREG in cancer cells have been associated with resistance to anti-EGFR therapy in patients. However, it remains unclear whether this abnormal expression also impacts CRC resistance to other chemotherapeutic drugs. The aim of this study is to examine whether AREG expression levels could be affected in CRC cells under Visfatin stimulation, thereby initiating the development of resistance to 5-fluororacil (5-FU). Through our results, we found that Visfatin indeed increases AREG expression, reducing the sensitivity of HCT-116 CRC cells to 5-FU cytotoxicity. Moreover, AREG upregulation is regulated by STAT3-CREB transcription factors activated by JNK1/2 and p38 signaling. This study highlights the significant role of AREG upregulation in CRC cells in initiating chemotherapeutic resistance to 5-FU under Visfatin stimulation. These findings provide a deeper understanding of drug resistance development in CRC under obese conditions and offer new insights into the correlation between an abnormal increase in AREG levels and the development of 5-FU-resistance in CRC cells, which should be considered in future clinical applications.

The Anticancer Poperties of Diosgenin on Colorectal Cancer Cells Induced by Wnt/Β Catenin Signaling Pathway

Background: Colorectal cancer (CC) is one of the most prevalent cancers globally. Due to the severe side effects and the development of drug resistance in CC treatments, current therapeutic strategies often prove ineffective. As a result, there is a growing interest in exploring traditional medicinal plants as alternative treatment options for various human diseases. Diosgenin, a bioactive compound derived from plants, has shown potential in inhibiting the growth of human CC cells. The Wnt/β-catenin signaling pathway plays a critical role in colorectal tumorigenesis. Objectives: This study investigates the effects of Diosgenin on the Wnt/β-catenin pathway in CC cells. Methods: Colorectal cancer cells were treated with Diosgenin, and cell viability and plasma membrane integrity were assessed using the MTT assay and lactate dehydrogenase (LDH) activity assay, respectively. Apoptosis was evaluated through Annexin V/PI staining. The expression of Wnt/β-catenin-related genes was analyzed by quantitative PCR (qPCR). Results: Diosgenin significantly inhibited CC cell viability in a time- and concentration-dependent manner after 24, 48, 72, and 96 hours of exposure (P < 0.05). The IC50 values were determined to be 203.55, 122.95, 70.11, and 7.34 µM at 24, 48, 72, and 96 hours, respectively. Diosgenin at its IC50 concentration induced a significant increase in cell apoptosis after 24 hours of treatment (P < 0.05). Additionally, it caused a significant reduction in the expression of β-catenin, cyclin D1, and Pin1 (βCP). Conclusions: Diosgenin exhibits anti-CC effects by inhibiting the expression of βCP genes involved in the Wnt/β-catenin pathway, suggesting its potential as a therapeutic agent for CC.

JAK Inhibitors for Myelofibrosis: Strengths and Limitations.

The landscape of myelofibrosis (MF) has changed since the discovery of the JAK2 V617F mutation and subsequent development of JAK inhibitors (JAKis). However, treatment with JAKis remain a challenge. In this review we critically analyze the strengths and limitations of currently available JAK inhibitors. In MF patients, JAK inhibitors have been associated with reduced symptom burden and spleen size, as well as improved survival. However, durability of response and development of treatment resistance remain an issue. Recently, there has been increased efforts to optimize treatment with the development of highly selective JAK inhibitors, as well as use of combination agents to counter disease resistance through targeting aberrant signaling pathways. Treatment of MF patients with JAKi therapy can be challenging but the development of more potent and selective JAK inhibitors, as well as combination therapies, represent exciting treatment advances in this field.

Prevalence, Virulence Genes, Drug Resistance and Genetic Evolution of Trueperella pyogenes in Small Ruminants in Western China.

Trueperella pyogenes is a significant opportunistic pathogen that causes substantial economic losses in animal agriculture due to its ability to infect various animal tissues and organs. Limited research has been conducted on the prevalence and biological characteristics of T. pyogenes isolated from sheep and goats. This study aimed to isolate T. pyogenes from clinical samples of sheep and goats in western China, examining genetic evolutionary relationships, antibiotic resistance, and virulence genes. Between 2021 and 2023, standard bacteriological methods were used to isolate and identify T. pyogenes from 316 samples (209 from goats and 107 from sheep) collected from 39 farms. Susceptibility to 14 antibiotics was tested using broth microdilution per CLSI guidelines, and PCR detected eight virulence genes. Whole-genome sequencing analyzed genetic relationships and gene carriage status in 39 isolates. The results indicated that 86 strains of T. pyogenes were isolated from 316 samples, yielding an isolation rate of 27.2% (goats n = 47, 22.5%; sheep n = 39, 36.4%). The virulence genes plo, cbpA, nanH, nanP, fimA, fimC, and fimE were present in 100%, 66.7%, 64.1%, 71.8%, 69.2%, 59.0%, and 82.1% of isolates, respectively, with none carrying the fimG gene. The dominant virulence genotype was plo/nanH/nanP/fimA/fimC/fimE. The isolates exhibited resistance to erythromycin (44.2%, 38/86), gentamicin (38.4%, 33/86), sulfamethoxazole/trimethoprim (37.2%, 32/86), tetracycline (32.6%, 28/86), and streptomycin (32.6%, 28/86), and low resistance to chloramphenicol (14.0%, 12/86), ciprofloxacin (7.0%, 6/86), penicillin (5.8%, 5/86), and clindamycin (4.7%, 4/86). All isolates were susceptible to cefotaxime, vancomycin, and linezolid. Among the 86 isolates, 37 (43.0%) displayed multidrug resistance (MDR) characteristics. The whole genome sequencing of 39 isolates identified eight types of resistance genes, including ant(2″)-Ia, ant(3″)-Ia, cmlA1, cmx, erm(X), lnu(A), sul1, and tet(W). Except for tet(W), erm(X), and sul1, the other resistance genes were reported for the first time in T. pyogenes isolated in China. The drug susceptibility test results and resistance gene detection for the isolated strains were consistent for tetracycline, erythromycin, gentamicin, and sulfisoxazole. Similar allelic profiles and genetic evolutionary relationships were found among isolates from different farms. This study highlights the antibiotic resistance status and virulence gene-carrying rate of Trueperella pyogenes, providing a basis for clinical medication.

Multifunctional MnGA Nanozymes for the Treatment of Ulcerative Colitis by Reducing Intestinal Inflammation and Regulating the Intestinal Flora.

In ulcerative colitis (UC), the formation of an inflammatory environment is due to the combined effects of excess production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), overproduction of proinflammatory cytokines, and disruption of immune system function. There are many kinds of traditional drugs for the clinical treatment of UC, but long-term drug use can cause toxic side effects and drug resistance and can also reduce patient compliance and other drawbacks. Hence, in light of the clinical challenges associated with UC, including the limitations of existing treatments, intense adverse reactions and the development of resistance to medications, no novel therapeutic agents that offer effective relief and maintain a high level of biosafety are urgently needed. Although many anti-inflammatory nanomedicines have been developed by researchers, the development of efficient and nontoxic nanomedicines is still a major challenge in clinical medicine. Using the natural product gallic acid and the metal compound manganese chloride, a highly effective and nontoxic multifunctional nanoenzyme was developed for the treatment of UC. Nanozymes can effectively eliminate ROS and RNS to reduce the inflammation of intestinal epithelial cells caused by oxidation, facilitate the restoration of the intestinal epithelial barrier through the upregulation of tight junction protein expression, and balance the intestinal microbiota to maintain the stability of the intestinal environment. Using a rodent model designed to mimic UC, we monitored body weight, colon length, the spleen index, and the degree of tissue damage and demonstrated that manganese gallate (MnGA) nanoparticles can reduce intestinal inflammation by clearing ROS and active nitrogen. Intestinal flora sequencing revealed that MnGA nanoparticles could regulate the intestinal flora, promote the growth of beneficial bacteria and decrease the levels of detrimental bacteria within the intestinal tract in a mouse model of UC. Thus, MnGA nanoparticles can maintain the balance of the intestinal flora. This study demonstrated that MnGA nanoparticles are excellent antioxidant and effective anti-inflammatory agents, have good biosafety, and can effectively treat UC.

Ceftriaxone versus cefepime or carbapenems for definitive treatment of low-risk AmpC-Harboring Enterobacterales bloodstream infections in hospitalized adults: A retrospective cohort study

ObjectiveTo compare outcomes of ceftriaxone to AmpC-stable therapies in patients with bacteremia caused by low-risk AmpC harboring Enterobacterales. MethodsIRB-approved, retrospective cohort of hospitalized patients ≥18 years old with Serratia marcescens, Morganella morganii, or Providencia spp. bacteremia from 1/1/2017-2/28/2024. Patients were compared by definitive therapy with ceftriaxone vs AmpC-stable therapy (cefepime, carbapenem). The primary endpoint was 30-day all-cause mortality; secondary endpoints were clinical failure and development of ceftriaxone resistance. Results163 patients were included; 33.1 % received ceftriaxone, 66.9 % AmpC-stable therapies. 30-day all-cause mortality was 9.3 % ceftriaxone vs 10.1 % AmpC stable patients (P = 0.87); ceftriaxone definitive therapy was not associated with 30-day all-cause mortality (adjOR, 0.79; 95 %CI, 0.23-2.3). There were no differences in clinical failure (9.3 % vs 21.1 %, P = 0.059) or relapsing infection (5.6 % vs 9.3 %, P = 0.55) between ceftriaxone and AmpC-stable treated patients. ConclusionsPatients treated with definitive ceftriaxone for low-risk AmpC Enterobacterales bacteremia had similar outcomes to AmpC stable therapies.

Targeted nanoliposomes of oncogenic protein degraders: Significant inhibition of tumor in lung-cancer bearing mice

With 60 % of non-small cell lung cancer (NSCLC) expressing epidermal growth factor receptor (EGFR), it has been explored as an important therapeutic target for lung tumors. However, even the well-established EGFR inhibitors tend to promptly develop resistance over time. Moreover, strategies that could impede resistance development and be advantageous for both EGFR-Tyrosine kinase inhibitor (TKI)-sensitive and mutant NSCLC patients are constrained. Based on the critical relationship between EGFR, c-MYC, and Kirsten rat sarcoma virus (K-Ras), simultaneous degradation of EGFR and Bromodomain-containing protein 4 (BRD4) using “Proteolysis Targeting Chimeras (PROTACs)” could be a promising approach. PROTACs are emerging class of oncoprotein degraders but very challanging to deliver in vivo. Compared to individual IC50s, strong synergism was observed at 1:1 ratio of BPRO and EPRO in NSCLC cell lines with diverse mutation. Significant inhibition of cell growth with higher cellular apoptosis was observed in 2D and 3D-based cell assays in nanomolar concentrations. EGFR activation assay revealed 47.60 % EGFR non-expressing cells confirming EGFR-degrading potential of EPRO. A lung cancer specific nanoliposomal formulation of EGFR and BRD4-degrading PROTACs (EPRO and BPRO) was prepared and characetrized. Successful encapsulation of the two highly lipophilic molecules was achieved in EGFR-targeting nanoliposomal carriers (T-BEPRO) using a modified hydration technique. T-BEPRO revealed a particle size of 109.22 ± 0.266 nm with enhanced cellular uptake and activity. Remarkably, parenterally delivered T-BEPRO in tumor-bearing mice showed a substantially higher % tumor growth inhibition (TGI) of 77.6 % with long-lasting tumor inhibitory potential as opposed to individual drugs.

How nanoscale plastics facilitate the evolution of antibiotic resistance?

The plastic can enhance the proliferation of antibiotic resistance genes (ARGs), however, the effect of nanoplastics (NPLs) on bacterial antibiotic resistance has not been clearly explained. Herein, we explored the effects and mechanisms of NPLs of different sizes (200 and 600 nm) on the evolution of antibiotic resistance in Serratia marcescens. The results indicated that the evolution of bacterial antibiotic resistance could be promoted under NPLs exposure, which the median of relative abundance of ARGs was 1.11–1.46 times compared to the treatment without NPLs. Transcriptomic analysis showed that the larger size of NPLs mainly increased the permeability of bacterial cell membranes to efflux antibiotics, thus potentiating antibiotic resistance. While, the smaller NPLs is more than that, its enhanced the expression of antibiotic resistance by modulating bacterial metabolic processes. The genome SNP analysis found that the NPLs could cause the genetic mutation occurrence to alter the membrane transport and metabolism processes, and it increased at a size of 200 nm more than at 600 nm NPLs. Importantly, we demonstrated that the horizontal transfer of ARGs was augmented due to the NPLs could dock to bacterial surface proteins and pull their movement to contact with other bacteria (binding energy of membrane proteins: −8.54 kcal/mol), especially the smaller size. It suggests that NPLs will also contribute to the proliferation of ARGs in the environment. This study provides data for understanding the risk of bacterial resistance.