Advances in traditional herbal formulation based nano-vaccine for cancer immunotherapy: Unraveling the enigma of complex tumor environment and multidrug resistance.

Cancer is attributed to uncontrolled cell growth and is among the leading causes of death with no known effective treatment while complex tumor microenvironment (TME) and multidrug resistance (MDR) are major challenges for developing an effective therapeutic strategy. Advancement in cancer immunotherapy has been limited by the over-activation of the host immune response that ultimately affects healthy tissues or organs and leads to a feeble response of the patient's immune system against tumor cells. Besides, traditional herbal medicines (THM) have been well-known for their essential role in the treatment of cancer and are considered relatively safe due to their compatibility with the human body. Yet, poor solubility, low bio-availability, and lack of understanding about their pathophysiological mechanism halt their clinical application. Moreover, considering the complex TME and drug resistance, the most precarious and least discussed concerns for developing THM-based nano-vaccination, are identification of specific biomarkers for drug inhibitory protein and targeted delivery of bioactive ingredients of THM on the specific sites in tumor cells. The concept of THM-based nano-vaccination indicates immunomodulation of TME by THM-based bioactive adjuvants, exerting immunomodulatory effects, via targeted inhibition of key proteins involved in the metastasis of cancer. However, this concept is at its nascent stage and very few preclinical studies provided the evidence to support clinical translation. Therefore, we attempted to capsulize previously reported studies highlighting the role of THM-based nano-medicine in reducing the risk of MDR and combating complex tumor environments to provide a reference for future study design by discussing the challenges and opportunities for developing an effective and safe therapeutic strategy against cancer.

Genomic characterization of a multidrug-resistant uropathogenic Escherichia coli and evaluation of Echeveria plant extracts as antibacterials.

Uropathogenic Escherichia coli (UPEC) is the most common bacterial agent associated with urinary tract infections, threatening public health systems with elevated medical costs and high morbidity rates. The successful establishment of the infection is associated with virulence factors encoded in its genome, in addition to antibacterial resistance genes, which could limit the treatment and resolution of the infection. In this sense, plant extracts from the genus Echeveria have traditionally been used to treat diverse infectious diseases. However, little is known about the effects of these extracts on bacteria and their potential mechanisms of action. This study aims to sequence a multidrug-resistant UPEC isolate (UTI-U7) and assess the multilocus sequence typing (MLST), virulence factors, antimicrobial resistance profile, genes, serotype, and plasmid content. Antimicrobial susceptibility profiling was performed using the Kirby-Bauer disk diffusion. The antibacterial and anti-adherent effects of the methanol extracts (ME) of Echeveria (E. craigiana, E. kimnachii, and E. subrigida) against UTI-U7 were determined. The isolate was characterized as an O25:H4-B2-ST2279-CH40 subclone and had resistant determinants to aminoglycosides, ß-lactams, fluoroquinolones/quinolones, amphenicols, and tetracyclines, which matched with the antimicrobial resistance profile. The virulence genes identified encode adherence factors, iron uptake, protectins/serum resistance, and toxins. Identified plasmids belonged to the IncF group (IncFIA, IncFIB, and IncFII), alongside several prophage-like elements. After an extensive genome analysis that confirmed the pathogenic status of UTI-U7 isolate, Echeveria extracts were tested to determine their antibacterial effects; as an extract, E. subrigida (MIC, 5 mg/mL) displayed the best inhibitory effect. However, the adherence between UTI-U7 and HeLa cells was unaffected by the ME of the E. subrigida extract.

Lycorine and homolycorine derivatives for chemo-sensitizing resistant human ovarian adenocarcinoma cells.

BACKGROUND: Multidrug resistance is the major obstacle to cancer chemotherapy. Modulation of P-glycoprotein and drug combination approaches have been considered important strategies to overcome drug resistance. PURPOSE: Aiming at generating a small library of Amaryllidaceae-type alkaloids to overcome drug resistance, two major alkaloids, isolated from Pancratium maritimum, lycorine (1), and 2α-10bα-dihydroxy-9-O-demethylhomolycorine (2), were derivatized, giving rise to nineteen derivatives (3 - 21). METHODS: The main chemical transformation of lycorine resulted from the cleavage of ring E of the diacetylated lycorine derivative (3) to obtain compounds that have carbamate and amine functions (5 - 16), while acylation of compound 2 provided derivatives 17 - 21. Compounds 1 - 21 were evaluated for their effects on cytotoxicity, and drug resistance reversal, using resistant human ovarian carcinoma cells (HOC/ADR), overexpressing P-glycoprotein (P-gp/ABCB1), as model. RESULTS: Excluding lycorine (1) (IC50 values of 1.2- 2.5 µM), the compounds were not cytotoxic or showed moderate/weak cytotoxicity. Chemo-sensitization assays were performed by studying the in vitro interaction between the compounds and the anticancer drug doxorubicin. Most of the compounds have shown synergistic interactions with doxorubicin. Compounds 5, 6, 9 - 14, bearing both carbamate and aromatic amine moieties, were found to have the highest sensitization rate, reducing the dose of doxorubicin 5-35 times, highlighting their potential to reverse drug resistance in combination chemotherapy. Selected compounds (4 - 6, 9 - 14, and 21), able of re-sensitizing resistant cancer cells, were further evaluated as P-gp inhibitors. Compound 11, which has a para­methoxy-N-methylbenzylamine moiety, was the strongest inhibitor. In the ATPase assay, compounds 9-11 and 13 behaved as verapamil, suggesting competitive inhibition of P-gp. At the same time, none of these compounds affected P-gp expression at the mRNA or protein level. CONCLUSIONS: This study provided evidence of the potential of Amaryllidaceae alkaloids as lead candidates for the development of MDR reversal agents.

Enhancing lathyrane structural diversity and MDR activity by combinatorial modification of lathyrane nucleus and ester side chain: A case study of Euphorbia Factor L1 and Euphorbia Factor L3.

The chemical transformation of lathyrane nucleus through reduction and oxidation reactions using Euphorbia Factor L1 (EFL1) and Euphorbia Factor L1 (EFL3) as examples were investigated, along with a co-modification strategy of lathyrane nucleus and its side ester chain. A total of 38 lathyrane derivatives (5-42) including 34 new compounds were obtained, which greatly enriched the structural diversity of the lathyrane-type diterpenoids. Cytotoxicity against drug-sensitive and drug (adriamycin, ADM) resistant MCF-7 cells showed that 23 out of 38 transformed derivatives possessed obvious cytotoxic activity with IC50 values ranging from 7.0 to 41.1 µM and 3.2 to 45.5 µM, respectively, against both cells, compared to the noncytotoxic EFL1 and EFL3. The multidrug resistance (MDR) reversing activities of these lathyrane derivatives were further evaluated in MCF-7/ADM. Three transformed compounds (reversal fold, RF = 151.33, 62.94 and 47.3 for 27, 37 and 42) showed markedly higher activity than EFL1 (RF = 32.92) and EFL3 (RF = 39.68). Structure-activity relationship study revealed an essential role of C-6/17 and C-12/13 double bonds on lathyrane nucleus for exerting MDR reversal activity. Western blotting analysis showed that 42 could reduce the expression level of P-glycoprotein (P-gp) in MCF-7/ADM cells; however, the most active compound 27 with an unnatural 5/7/7/4 fused-ring diterpenoid skeleton, had no inhibitory effect on P-gp expression.

Antimicrobial and Synergistic Effects of Syzygium cumini, Moringa oleifera, and Tinospora cordifolia Against Different Candida Infections.

Introduction The burden of multiple drug resistance in human pathogens has necessitated the search for and development of antimicrobial agents with a wide range of structural classes and potentials to selectively act on the several mechanisms of actions exhibited by the pathogens. However, most synthetic antimicrobial agents have been linked with adverse side effects and high costs, furthering the need to explore more options. Syzygium cumini, Moringa oleifera, and Tinospora cordifolia are three medicinal plants used in traditional medicine systems for various infectious diseases. They contain various phytochemicals that exhibit antimicrobial activities against various bacteria, fungi, and parasites. The mechanisms of their antimicrobial action may involve the disruption of microbial cell walls and membranes, the inhibition of microbial enzyme and biofilm formation, the modulation of microbial gene expression and quorum sensing, and the induction of microbial cell death. Therefore, the present study evaluated the potentials of aqueous and ethanol extracts of S. cumini, M. oleifera, and T. cordifolia in managing infections as measured by their inhibitory effects on species. Materials and method Syzygium cumini, M. oleifera, and T. cordifolia were obtained and authenticated, and their aqueous and ethanol extracts were prepared. The antibacterial properties of the aqueous and ethanol extracts were examined. In addition to broth microdilution and biofilm development experiments, we also employed disk diffusion and agar-well diffusion techniques. The inocula of various species, including krusei, parapsilosis, utilis, albicans, and glabrata, were prepared for these assays. The synergistic effect of plant extracts with fluconazole was also evaluated. Results Syzygium cumini, M. oleifera, and T. cordifolia emerge as promising sources for the development of effective and sustainable antimicrobial interventions. Interestingly, the aqueous and ethanol extracts were effective against the selected species. Also, the synergistic combination of plant extracts with fluconazole was observed to triple the potency of the extracts. Furthermore, the potency of the plant extract as an antifungal and synergistic agent was ranked as S. cumini > M. oleifera > T. cordifolia. Conclusively, the plant extracts are effective in the management of opportunistic fungal infections.

Antimicrobial potential of phytocompounds of Acorus calamus: in silico approach.

Medicinal plants are used from prehistoric time to cure various life-threatening bacterial diseases. Acorus calamus is an important medicinal plant widely used to cure gastrointestinal, respiratory, kidney and liver disorders. The objective of the current research was to investigate the interaction of major phytoconstituents of Acorus calamus with bacterial (6VJE) and fungal (1EA1) protein targets. Protein-ligand interactions were estimated using the AutoDock software, drug likeness was predicted by using the molinspiration server and toxicity was predicted with the swissADME and protox II servers. MD simulation of phytocompounds with the best profiles was done on the GROMACS software for 100 ns. Molecular docking results showed among all the selected major phytoconstituents, that ß-cadinene showed best binding interaction in complex with bacterial (6VJE) and fungal (1EA1) protein targets with binding energy -7.66 ± 0.1 and -7.73 ± 0.15 kcal mol-1, respectively. Drug likeness and toxicity predictions showed that ß-cadinene follows all rules of drug likeness and toxicity. MD simulation study revealed that ß-cadinene fit in binding pocket of bacterial and fungal targets and found to be stable throughout the duration of the simulation. Based on the observations from this in-silico study it is being proposed that ß-cadinene, a major phytocompound of Acorus calamus, can be considered for the treatment of bacterial and fungal infections since the study shows that it might be one of the compounds that contributes majorly to the plant's biological activity. This study needs in vitro and in vivo validation.Communicated by Ramaswamy H. Sarma.

Review of treatment options for a multidrug-resistant fungus: Candida auris.

Candida auris is a widely distributed, highly lethal, multidrug-resistant fungal pathogen. It was first identified in 2009 when it was isolated from fluid drained from the external ear canal of a patient in Japan. Since then, it has caused infectious outbreaks in over 45 countries, with mortality rates approaching 60%. Drug resistance is common in this species, with a large proportion of isolates displaying fluconazole resistance and nearly half are resistant to two or more antifungal drugs. In this review, we describe the drug resistance mechanism of C. auris and potential small-molecule drugs for treating C. auris infection. Among these antifungal agents, rezafungin was approved by the US Food and Drug Administration (FDA) for the treatment of candidemia and invasive candidiasis on March 22, 2023. Ibrexafungerp and fosmanogepix have entered phase III clinical trials.

Mosloflavone from Fissistigma petelotii ameliorates oncogenic multidrug resistance by STAT3 signaling modulation and P-glycoprotein blockade.

BACKGROUND: Oncogenic multidrug resistance (MDR) is a tough question in cancer therapy. However, no effective medications targeting oncogenic MDR are currently available. Studies have demonstrated that mosloflavone exerts anti-inflammatory effects, yet, its potential to ameliorate MDR remains unclear. PURPOSE: This study aimed to access the capability and elucidate molecular mechanisms of mosloflavone as a MDR resensitizing candidate. METHODS: We investigated the ability of mosloflavone to reverse oncogenic MDR and investigated its underlying mechanisms through cytotoxicity assay, cell cycle assay, apoptosis assay, and zebrafish xenograft model. The modulatory interplay between mosloflavone and P-gp was investigated through analysis of calcein-AM uptake, substrate efflux, ATPase assays, and molecular docking simulation. RESULTS: Mosloflavone inhibited P-gp efflux function in an uncompetitive manner without altering ABCB1 gene expression. In addition, it stimulated P-gp ATPase activity by binding to an active site distinct from that of verapamil. Regarding MDR reversal potential, mosloflavone resensitized MDR cancer cells to chemotherapies by arresting cell cycle and triggering apoptosis, possibly by enhancing reactive oxygen species accumulation and reducing phospho-STAT3. Moreover, in the zebrafish xenograft model, mosloflavone significantly potentiated the antitumor effect of paclitaxel. CONCLUSION: Our findings underscore the potential of mosloflavone as a novel dual modulator of STAT3 and P-gp, indicating it is a promising candidate for overcoming MDR in cancer treatment.

Harnessing small extracellular vesicles for pro-oxidant delivery: novel approach for drug-sensitive and resistant cancer therapy.

Multidrug resistance (MDR) is an inevitable clinical problem in chemotherapy due to the activation of abundant P-glycoprotein (P-gp) that can efflux drugs. Limitations of current cancer therapy highlight the need for the development of a comprehensive cancer treatment strategy, including drug-resistant cancers. Small extracellular vesicles (sEVs) possess significant potential in surmounting drug resistance as they can effectively evade the efflux mechanism and transport small molecules directly to MDR cancer cells. One mechanism mediating MDR in cancer cells is sustaining increased levels of reactive oxygen species (ROS) and maintenance of the redox balance with antioxidants, including glutathione (GSH). Herein, we developed GSH-depleting benzoyloxy dibenzyl carbonate (B2C)-encapsulated sEVs (BsEVs), which overcome the efflux system to exert highly potent anticancer activity against human MDR ovarian cancer cells (OVCAR-8/MDR) by depleting GSH to induce oxidative stress and, in turn, apoptotic cell death in both OVCAR-8/MDR and OVCAR-8 cancer cells. BsEVs restore drug responsiveness by inhibiting ATP production through the oxidation of nicotinamide adenine dinucleotide with hydrogen (NADH) and inducing mitochondrial dysfunction, leading to the dysfunction of efflux pumps responsible for drug resistance. In vivo studies showed that BsEV treatment significantly inhibited the growth of OVCAR-8/MDR and OVCAR-8 tumors. Additionally, OVCAR-8/MDR tumors showed a trend towards a greater sensitivity to BsEVs compared to OVCAR tumors. In summary, this study demonstrates that BsEVs hold tremendous potential for cancer treatment, especially against MDR cancer cells.

Overcoming multi drug resistance mediated by ABC transporters by a novel acetogenin- annonacin from Annona muricata L.

ETHNOPHARMACOLOGICAL RELEVANCE: Multi-Drug Resistance (MDR), mediated by P-glycoprotein (P-gp) is one of the barriers to successful chemotherapy in colon cancer patients. Annona muricata L. (A.muricata), commonly known as soursop/Graviola, is a medicinal plant that has been traditionally used in treating diverse diseases including cancer. Phytochemicals of A.muricata (Annonaceous Acetogenins-AGEs) have been well-reported for their anti-cancer effects on various cancers. AIM OF THE STUDY: The study aimed to examine the effect of AGEs in reversing MDR in colorectal cancer cells. METHODS: Based on molecular docking and molecular dynamic simulation, the stability of annonacin upon P-gp was investigated. Further in vitro studies were carried in oxaliplatin-resistant human colon cancer cells (SW480R) to study the biological effect of annonacin, in reversing drug resistance in these cells. RESULTS: Molecular docking and simulation studies have indicated that annonacin stably interacted at the drug binding site of P-gp. In vitro analysis showed that annonacin was able to significantly reduce the expression of P-gp by 2.56 folds. It also induced apoptosis in the drug-resistant colon cancer cells. Moreover, the intracellular accumulation of P-gp substrate (calcein-AM) was observed to increase in resistant cells upon treatment with annonacin. CONCLUSION: Our findings suggest that annonacin could inhibit the efflux of chemotherapeutic drugs mediated by P-gp and thereby help in reversing MDR in colon cancer cells. Further in vivo studies are required to decipher the underlying mechanism of annonacin in treating MDR cancers.

pH-Responsive Polypropylene Sulfide Magnetic Nanocarrier-Mediated Chemo-Hyperthermia Kills Breast Cancer Stem Cells by Long-Term Reversal of Multidrug Resistance and Chemotherapy Resensitization.

Cancer stem cells (CSCs) present a formidable challenge in cancer treatment due to their inherent resistance to chemotherapy, primarily driven by the overexpression of ABC transporters and multidrug resistance (MDR). Despite extensive research on pharmacological small-molecule inhibitors, effectively managing MDR and improving chemotherapeutic outcomes remain elusive. On the other hand, magnetic hyperthermia (MHT) holds great promise as a cancer therapeutic, but there is limited research on its potential to reverse MDR in breast CSCs and effectively eliminate CSCs through combined chemo-hyperthermia. To address these gaps, we developed tumor microenvironment-sensitive, drug-loaded poly(propylene sulfide) (PPS)-coated magnetic nanoparticles (PPS-MnFe). These nanoparticles were employed to investigate hyperthermia sensitivity and MDR reversion in breast CSCs, comparing their performance to that of small-molecule inhibitors. Additionally, we explored the efficacy of combined chemo-hyperthermia in killing CSCs. CSC-enriched breast cancer cells were subjected to low-dose MHT at 42 °C for 30 min and then treated with the chemical MDR inhibitor salinomycin (SAL). The effectiveness of each treatment in inhibiting MDR was assessed by measuring the efflux of the MDR substrate, rhodamine 123 (R123) dye. Notably, MHT induced a prolonged reversal of MDR activity compared with SAL treatment alone. After successfully inhibiting MDR, the breast CSCs were exposed to chemotherapy using paclitaxel to trigger synergistic cell death. The combination of MHT and chemotherapy demonstrated remarkable reductions in stemness properties, MDR reversal, and the effective eradication of breast CSCs in this innovative dual-modality approach.

Reversal of Multidrug Resistance by the Synergistic Effect of Reversan and Hyperthermia to Potentiate the Chemotherapeutic Response of Doxorubicin in Glioblastoma and Glioblastoma Stem Cells.

The glioblastoma stem cell (GSC) population in glioblastoma multiforme (GBM) poses major complication in clinical oncology owing to increased resistance to chemotherapeutic drugs, thereby limiting treatment in patients with recurring glioblastoma. To completely eradicate glioblastoma, a single therapy module is not enough; therefore, there is a need to develop a multimodal approach to eliminate bulk tumors along with the CSC population. With an aim to target transporters associated with multidrug resistance (MDR), such as P-glycoprotein (P-gp), a small-molecule inhibitor, reversan (RV) was used along with multifunctional magnetic nanoparticles (MNPs) for hyperthermia (HT) therapy and targeted drug delivery. Higher efflux of free doxorubicin (Dox) from the cells was stabilized by encapsulation in PPS-MnFe nanoparticles, whose physicochemical properties were determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Treatment with RV also enhanced the cellular uptake of PPS-MnFe-Dox, whereas RV and magnetic hyperthermia (MHT) together showed prolonged retention of fluorescence dye, Rhodamine123 (R123), in glioblastoma cells compared with individual treatment. Overall, in this work, we demonstrated the synergistic action of RV and HT to combat MDR in GBM and GSCs, and chemo-hyperthermia therapy enhanced the cytotoxic effect of the chemotherapeutic drug Dox (with lower effective concentration) and induced a higher degree of apoptosis compared to single-drug dosage.

Antibacterial Efficiency of Tanacetum vulgare Essential Oil against ESKAPE Pathogens and Synergisms with Antibiotics.

Medicinal plants with multiple targets of action have become one of the most promising solutions in the fight against multidrug-resistant (MDR) bacterial infections. Tanacetum vulgare (Tansy) is one of the medicinal plants with antibacterial qualities that deserve to be studied. Thus, this research takes a closer look at tansy extract's composition and antibacterial properties, aiming to highlight its potential against clinically relevant bacterial strains. In this respect, the antibacterial test was performed against several drug-resistant pathogenic strains, and we correlated them with the main isolated compounds, demonstrating the therapeutic properties of the extract. The essential oil was extracted via hydrodistillation, and its composition was characterized via gas chromatography. The main isolated compounds known for their antibacterial effects were α-Thujone, ß-Thujone, Eucalyptol, Sabinene, Chrysanthenon, Camphor, Linalool oxide acetate, cis-Carveol, trans-Carveyl acetate, and Germacrene. The evaluation of the antibacterial activity was carried out using the Kirby-Bauer and binary microdilution methods on Gram-positive and Gram-negative MDR strains belonging to the ESKAPE group (i.e., Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). Tansy essential oil showed MIC values ranging from 62.5 to 500 µg/mL against the tested strains. Synergistic activity with different classes of antibiotics (penicillins, cephalosporins, carbapenems, monobactams, aminoglycosides, and quinolones) has also been noted. The obtained results demonstrate that tansy essential oil represents a promising lead for developing new antimicrobials active against MDR alone or in combination with antibiotics.

Silver-cored Ziziphus spina-christi extract-loaded antimicrobial nanosuspension: overcoming multidrug resistance.

Aims: To synthesize a silver-cored nanosuspension utilizing Ziziphus spina-christi fresh-leaf extract and evaluate their antimicrobial activity against multidrug-resistant pathogenic microbes. Materials and Methods: The prepared nanosuspension was analyzed by spectro-analytical techniques and tested for antimicrobial activity and resistance to biofilm formation. The leaf extract and nanosuspension were tested separately and together as a mixture. Results: Constituent nanoparticles were average-sized (∼34 nm) and were active against both Gram-positive and Gram-negative microbes and yeast. Candida albicans showed a 24.50 ± 1.50 mm inhibition zone, followed by Escherichia coli and Staphylococcus aureus. Increased bioactivity with the highest multifold increments, 150%, for erythromycin against all tested microbes was observed. Carbenicillin and trimethoprim showed 166%- and 300%-fold increments for antimicrobial activity against Pseudomonas aeruginosa, respectively. Conclusion: The nanosuspension exhibited strong potential as an antimicrobial agent and overcame multidrug resistance.

Ziziphus spina-christi leaf extract-coated silver nanoparticles were synthesized using an environment-friendly method, and the preparation was effective against Escherichia coli, Staphylococcus aureus and Candida albicans. The prepared formulation showed increased antimicrobial activity at a 150­300% increase compared with leaf extract-only activity. The prepared suspension was also active against Pseudomonas aeruginosa, the multidrug-resistant microbe, and has the potential to treat drug-resistant microbial infections.

Potential of Flavonoids as Promising Phytotherapeutic Agents to Combat Multidrug-Resistant Infections.

BACKGROUND: Considering the limited number of current effective treatments, Multidrug- Resistant (MDR) illnesses have grown to be a serious concern to public health. It has become necessary to look for new antimicrobial drugs because of the emergence of resistance to numerous kinds of antibiotics. The use of flavonoids is one phytotherapeutic strategy that has been researched as a potential remedy for this issue. Secondary plant compounds called flavonoids have been found to have an antibacterial effect against resistant microorganisms. OBJECTIVE: This review seeks to give readers a glimpse into contemporary studies on flavonoids' potential to fight MDR infections. METHODS: A systematic search was conducted on electronic databases (PubMed, Scopus, and Google Scholar) using relevant keywords such as flavonoids, MDR infections, antimicrobial activity, and resistance microbes. Studies that investigated the antimicrobial activity of flavonoids against resistant microbes were included in this review. RESULTS: Most research found that flavonoids have antibacterial efficacy against resistant microorganisms, and some also showed that they have synergistic benefits with traditional antibiotics. The flavonoids quercetin, kaempferol, apigenin, and luteolin were the most often investigated ones. According to research, flavonoids affect microbial gene expression, inhibit microbial enzymes, and disrupt the integrity of microbial cell membranes. Additionally, a few studies have noted the flavonoids' low toxicity and safety. CONCLUSION: For the treatment of infections that are resistant to many drugs, flavonoids constitute a promising class of phytotherapeutic agents. To develop flavonoid-based treatment methods for treating MDR illnesses and assess the potential of flavonoids as adjuvants to conventional antimicrobial drugs, more study is required.

Clinical, epidemiological, and laboratory profiles of bacterial infection or colonization among patients hospitalized in COVID-19 and non-COVID-19 intensive care units (ICUs) in Southeast Pará / Perfis clínico, epidemiológico e laboratorial de infecção ou colonização bacteriana em pacientes internados em unidades de terapia intensiva (UTIs) COVID-19 e não COVID-19 no sudeste do Pará

Objectives: To compare the clinical, epidemiological, and laboratory profiles of bacterial infection or colonization among patients hospitalized in COVID-19 and non-COVID-19 intensive care units (ICUs) in Southeast Pará, Brazil. Methods:This was a retrospective analytical study based on the analyses of electronic medical records and microbiological reports of patients admitted to the ICU of a regional hospital located in Pará in the Brazilian Amazon due to complications associated with COVID-19 and other causes from March 2020 to December 2021. The sample consisted of data from the medical records of 343 patients collected after approval by the ethics and research committee (opinion number 5281433) was granted. The data extracted from the bacteriological and antibiogram culture reports were analyzed to characterize the clinical-epidemiological profile of the patients. The data were transferred and tabulated in Microsoft Excel 2019 to conduct a descriptive analysis, and the associated statistical analyses were performed using Stata 17.0 statistical soft-ware. Results: Of the total patients, 59.5% were hospitalized in the COVID-19 ICU and 40.5% were hospitalized in the non-COVID-19 ICU. Most individuals admitted to the COVID-19 ICU and non-COVID-19 ICU were aged between 66 and 78 years and between 54 and 66 years, respectively. The hospitalization duration in the COVID-19 ICU was fewer than 15 days, whereas that in the non-COVID-19 ICU was 15 to 30 days. Deaths were more frequent in the Covid-19 ICU compared to the non-Covid-19 ICU (64% versus 41%). In contrast, hospital discharge was more frequent in the non-Covid-19 ICU (58.3% versus 34.8%).The most prevalent comorbidity in both ICUs was circulatory system disease. Gram-negative bacteria were the most frequent etiological agent in both groups and were present in 63.1% of the cultures analyzed. Regarding the phenotypic profile of resistance, carbapenemase production was detected in 43.0% of the cultures analyzed. Multidrug resistance against antimicrobial drugs was more frequent in the non-COVID-19 ICU (55.7%). Most of the antimicrobial drug prescriptions for were empirical. Conclusions: The recurrence of secondary infections and bacterial colonization in both COVID-19 and non-COVID-19 ICU patients should not be underestimated. The clinical, microbiological, and bacterial resistance profiles elucidated in this study highlight the need to develop and implement holistic and assertive strategies to control and mitigate these problems. Which will contribute to an improved prognosis for patients and quality of life patients (AU).

Objetivos: Comparar o perfil clínico, epidemiológico e laboratorial das infecções ou colonizações bacterianas entre pacientes internados em UTI COVID-19 e não-COVID-19 no Sudeste do Pará, Brasil. Métodos: Trata-se de um estudo analítico retrospectivo baseado na análise de prontuários eletrônicos e laudos microbiológicos de pacientes internados em um hospital regional localizado no Pará, na Amazônia brasileira, devido a complicações associadas à COVID-19 e outras causas no período de março de 2020 a dezembro de 2021. A amostra foi constituída por dados dos prontuários de 343 pacientes coletados após aprovação pelo Comitê de ética em Pesquisa (parecer número 5281433). Os dados extraídos dos laudos de cultura bacteriológica e antibiograma foram analisados para caracterizar o perfil clínico-epidemiológico dos pacientes. Foram realizadas análises descritivas e inferenciais utilizando o Stata 17.0 statistical software. Resultados: Do total de pacientes, 59,5% estavam internados na UTI COVID-19 e 40,5% na UTI não-COVID-19. A maioria dos indivíduos apresentavam idades entre 54 e 78. O tempo de internação na UTI COVID-19 foi inferior a 15 dias, enquanto na UTI não-CO-VID-19 foi de 15 a 30 dias. Os óbitos foram mais frequentes na UTI Covid-19 em relação à UTI não-Covid-19 (64% versus 41%). Em contrapartida, a alta hospitalar foi mais frequente na UTI não Covid-19 (58,3% versus 34,8%). A comorbidade mais prevalente em ambas as UTIs foi a doença do aparelho circulatório. As bactérias Gram-negativas foram os agentes etiológicos mais frequentes em ambos os grupos e estiveram presentes em 63,1% das culturas analisadas. Em relação ao perfil fenotípico de resistência, a produção de carbapenemase foi detectada em 43,0% das culturas analisadas. A multirresistência aos antimicrobianos foi mais frequente na UTI não COVID-19 (55,7%). A maioria das prescrições de antimicrobianos foram empíricas. Conclusões: A recorrência de infecções secundárias e colonizações bacterianas em pacientes com COVID-19 e não COVID-19 em UTIs não devem ser subestimadas. Os perfis de resistência bacteriana elucidados neste estudo destacam a necessidade da implementação de estratégias holísticas e assertivas visando o controle e mitigação dessa problemática, o que contribuirá para a melhoria do prognóstico, bem como, a qualidade e segurança dos paciente (AU).

A facile, flexible, and multifunctional thermo-chemotherapy system for customized treatment of drug-resistant breast cancer.

Anticancer drug resistance invariably emerges and poses a significant barrier to curative therapy for various breast cancers. This results in a lack of satisfactory therapeutic medicine for cancer treatment. Herein, a universal vector system for drug-resistance breast cancer was designed to meet the needs of reversed multidrug resistance, thermo-chemotherapy, and long-term drug release behavior. The vector system comprises polycaprolactone (PCL) nanofiber mesh and magnetic nanoparticles (MNPs). PCL has excellent biocompatibility and electrospinning performance. In this study, MNPs were tailored to be thermogenic in response to an alternating magnetic field (AMF). PCL nanofiber can deliver various chemotherapy drugs, and suitable MNPs encapsulated in the nanofiber can generate hyperthermia and synergistic effect with those chemotherapy drugs. Therefore, a more personalized treatment system can be developed for different breast malignancies. In addition, the PCL nanofiber mesh (NFM) enables sustained release of the drugs for up two months, avoiding the burden on patients caused by repeated administration. Through model drugs doxorubicin (DOX) and chemosensitizers curcumin (CUR), we systematically verified the therapeutic effect of DOX-resistance breast cancer and inhibition of tumor generation in vivo. These findings represent a multifaceted platform of importance for validating strategic reversed MDR in pursuit of promoted thermo-chemotherapeutic outcomes. More importantly, the low cost and excellent safety and efficacy of this nanofiber mesh demonstrate that this can be customized multi-function vector system may be a promising candidate for refractory cancer therapy in clinical.

The scope of antimicrobial resistance in residential aged care facilities determined through analysis of Escherichia coli and the total wastewater resistome.

IMPORTANCE: Antimicrobial resistance (AMR) is a global threat that imposes a heavy burden on our health and economy. Residential aged care facilities (RACFs), where frequent inappropriate antibiotic use creates a selective environment that promotes the development of bacterial resistance, significantly contribute to this problem. We used wastewater-based epidemiology to provide a holistic whole-facility assessment and comparison of antimicrobial resistance in two RACFs and a retirement village. Resistant Escherichia coli, a common and oftentimes problematic pathogen within RACFs, was isolated from the wastewater, and the phenotypic and genotypic AMR was determined for all isolates. We observed a high prevalence of an international high-risk clone, carrying an extended-spectrum beta-lactamase in one facility. Analysis of the entire resistome also revealed a greater number of mobile resistance genes in this facility. Finally, both facilities displayed high fluoroquinolone resistance rates-a worrying trend seen globally despite measures in place aimed at limiting their use.

Antimicrobial peptides in combination with citronellal efficiently kills multidrug resistance bacteria.

BACKGROUND: Antimicrobial peptides (AMPs) are considered as the most potential alternatives to antibiotics, but they have several drawbacks, including high cost, medium antimicrobial efficacy, poor cell selectivity, which limit clinical application. To overcome the above problems, combination therapy of AMPs with adjuvants might maximize the effectiveness of AMPs. We found that citronellal can substantially potentiate the ZY4R peptide efficacy against Escherichia coli ATCC25922. However, it is unclear whether ZY4R/citronellal combination poses synergistic antimicrobial effects against most bacteria, and their synergy mechanism has not been elucidated. PURPOSE: To investigate synergistic antimicrobial efficacies, biosafety, and synergy mechanism of ZY4R/citronellal combination. METHOD: Checkerboard, time-kill curves, cytotoxicity assays, and in vivo animal models were conducted to assess synergistic antimicrobial effects and biosafety of the ZY4R/citronellal combination. To evaluate their synergy mechanism, a series of cell-based assays and transcriptome analysis were performed. RESULTS: ZY4R/citronellal combination exhibited synergistic antimicrobial effects against 20 clinically significant pathogens, with the fractional inhibitory concentration index (FICI) ranging from 0.313 to 0.047. Meanwhile, ZY4R/citronellal combination enhanced antimicrobial efficacies without compromising cell selectivity, contributing to decreasing drug dosage and improving biosafety. Compared with ZY4R (4 mg/kg) and citronellal (25 mg/kg) alone, ZY4R (4 mg/kg)/citronellal (25 mg/kg) combination significantly decreased the bacterial load in peritoneal fluid, liver, and kidney (P < 0.05) and alleviated pathological damage of the organs of mice. Mechanistic studies showed that ZY4R allowed citronellal to pass through the outer membrane rapidly and acted on the inner membrane together with citronellal, causing more potent membrane damage. The membrane damage prompted the continuous accumulation of citronellal in cells, and citronellal further induced energy breakdown and inhibited exopolysaccharide (EPS) production, which aggravated ZY4R-induced outer membrane damage, thereby resulting in bacterial death. CONCLUSIONS: ZY4R/citronellal combination exhibited broad-spectrum synergy with a low resistance development and high biosafety. Their synergy mechanism acted on two important cellular targets (energy metabolism and membrane integrity). Combination therapy of ZY4R with citronellal may be a promising mixture to combat bacterial infections facing an antibiotic-resistance crisis.

The Challenge of Overcoming Antibiotic Resistance in Carbapenem-Resistant Gram-Negative Bacteria: "Attack on Titan".

The global burden of bacterial resistance remains one of the most serious public health concerns. Infections caused by multidrug-resistant (MDR) bacteria in critically ill patients require immediate empirical treatment, which may not only be ineffective due to the resistance of MDR bacteria to multiple classes of antibiotics, but may also contribute to the selection and spread of antimicrobial resistance. Both the WHO and the ECDC consider carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant Acinetobacter baumannii (CRAB) to be the highest priority. The ability to form biofilm and the acquisition of multiple drug resistance genes, in particular to carbapenems, have made these pathogens particularly difficult to treat. They are a growing cause of healthcare-associated infections and a significant threat to public health, associated with a high mortality rate. Moreover, co-colonization with these pathogens in critically ill patients was found to be a significant predictor for in-hospital mortality. Importantly, they have the potential to spread resistance using mobile genetic elements. Given the current situation, it is clear that finding new ways to combat antimicrobial resistance can no longer be delayed. The aim of this review was to evaluate the literature on how these pathogens contribute to the global burden of AMR. The review also highlights the importance of the rational use of antibiotics and the need to implement antimicrobial stewardship principles to prevent the transmission of drug-resistant organisms in healthcare settings. Finally, the review discusses the advantages and limitations of alternative therapies for the treatment of infections caused by these "titans" of antibiotic resistance.