UNASSIGNED: RNA interference (RNAi) stands as a widely employed gene interference technology, with small interfering RNA (siRNA) emerging as a promising tool for cancer treatment. However, the inherent limitations of siRNA, such as easy degradation and low bioavailability, hamper its efficacy in cancer therapy. To address these challenges, this study focused on the development of a nanocarrier system (HLM-N@DOX/R) capable of delivering both siRNA and doxorubicin for the treatment of breast cancer.
UNASSIGNED: The study involved a comprehensive investigation into various characteristics of the nanocarrier, including shape, diameter, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), encapsulation efficiency, and drug loading. Subsequently, in vitro and in vivo studies were conducted on cytotoxicity, cellular uptake, cellular immunofluorescence, lysosome escape, and mouse tumor models to evaluate the efficacy of the nanocarrier in reversing tumor multidrug resistance and anti-tumor effects.
UNASSIGNED: The results showed that HLM-N@DOX/R had a high encapsulation efficiency and drug loading capacity, and exhibited pH/redox dual responsive drug release characteristics. In vitro and in vivo studies showed that HLM-N@DOX/R inhibited the expression of P-gp by 80%, inhibited MDR tumor growth by 71% and eliminated P protein mediated multidrug resistance.
UNASSIGNED: In summary, HLM-N holds tremendous potential as an effective and targeted co-delivery system for DOX and P-gp siRNA, offering a promising strategy for overcoming MDR in breast cancer.

OBJECTIVE: To describe the prevalence and antibiotic resistance profiles of Pseudomonas aeruginosa isolated from the Asia Cornea Society Infectious Keratitis Study (ACSIKS).
METHODS: All bacterial isolates from ACSIKS underwent repeat microbiological identification in a central repository in Singapore. Minimum inhibitory concentration (MIC) determination was conducted for isolates of P. aeruginosa against thirteen antibiotics from 6 different classes, and categorized based on Clinical Laboratory Standard Institutes\' reference ranges. The percentage rates of resistance (non-susceptibility) to each antibiotic included isolates of both intermediate and complete resistance. Multi-drug resistance (MDR) was defined as non-susceptibility to at least one agent in three or more antimicrobial classes.
RESULTS: Of the 1493 unique bacterial specimens obtained from ACSIKS, 319 isolates were of P. aeruginosa. The majority of isolates were from centers in India (n = 118, 37%), Singapore (n = 90, 28.2%), Hong Kong (n = 31, 9.7%) and Thailand (n = 30, 9.4%). The cumulative antibiotic resistance rate was the greatest for polymyxin B (100%), ciprofloxacin (17.6%) and moxifloxacin (16.9%), and lowest for cefepime (11.6%) and amikacin (13.5%). Isolates from India demonstrated the highest antibiotic resistance rates of all the centers, and included moxifloxacin (47.5%) and ciprofloxacin (39.8%). Forty-eight of the 59 MDR isolates also originated from India. Antibiotic resistance rates were significantly lower in the other ACSIKS centers, and were typically less than 10%.
CONCLUSIONS: The antibiotic resistance profiles of P. aeruginosa varied between different countries. While it was low for most countries, substantial antibiotic resistance and a significant number of multi-drug resistant isolates were noted in the centers from India.

The P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has emerged as a significant impediment to the efficacy of cancer chemotherapy in clinical therapy, which could promote the development of effective agents for MDR reversal. In this work, we reported the exploration of novel pyrazolo [1,5-a]pyrimidine derivatives as potent reversal agents capable of enhancing the sensitivity of ABCB1-mediated MDR MCF-7/ADR cells to paclitaxel (PTX). Among them, compound 16q remarkably increased the sensitivity of MCF-7/ADR cells to PTX at 5 μM (IC50 = 27.00 nM, RF = 247.40) and 10 μM (IC50 = 10.07 nM, RF = 663.44). Compound 16q could effectively bind and stabilize ABCB1, and does not affect the expression and subcellular localization of ABCB1 in MCF-7/ADR cells. Compound 16q inhibited the function of ABCB1, thereby increasing PTX accumulation, and interrupting the accumulation and efflux of the ABCB1-mediated Rh123, thus resulting in exhibiting good reversal effects. In addition, due to the potent reversal effects of compound 16q, the abilities of PTX to inhibit tubulin depolymerization, and induce cell cycle arrest and apoptosis in MCF-7/ADR cells under low-dose conditions were restored. These results indicate that compound 16q might be a promising potent reversal agent capable of revising ABCB1-mediated MDR, and pyrazolo [1,5-a]pyrimidine might represent a novel scaffold for the discovery of new ABCB1-mediated MDR reversal agents.

Mild photothermal therapy (PTT) shows the potential for chemosensitization by tumor-localized P-glycoprotein (P-gp) modulation. However, conventional mild PTT struggles with real-time uniform temperature control, obscuring the temperature-performance relationship and resulting in thermal damage. Besides, the time-performance relationship and the underlying mechanism of mild PTT-mediated P-gp reversal remains elusive. Herein, we developed a temperature self-limiting lipid nanosystem (RFE@PD) that integrated a reversible organic heat generator (metal-phenolic complexes) and metal chelator (deferiprone, DFP) encapsulated phase change material. Upon NIR irradiation, RFE@PD released DFP for blocking ligand-metal charge transfer to self-limit temperature below 45 °C, and rapidly reduced P-gp within 3 h via Ubiquitin-proteasome degradation. Consequently, the DOX·HCl-loaded thermo-chemotherapeutic lipid nanosystem (RFE@PD-DOX) led to dramatically improved drug accumulation and 5-fold chemosensitization in MCF-7/ADR tumor models by synchronizing P-gp reversal and drug pulse liberation, achieving a tumor inhibition ratio of 82.42%. This lipid nanosystem integrated with \"intrinsic temperature-control\" and \"temperature-responsive pulse release\" casts new light on MDR tumor therapy.

Multidrug resistance (MDR) of tumors is one of the main reasons for the failure of chemotherapy. Multidrug resistance refers to the cross-resistance of tumor cells to multiple antitumor drugs with different structures and mechanisms of action. Current strategies to reverse multidrug resistance in tumors include MDR inhibitors and RNAi technology. siRNA is a small molecule RNA that is widely used in RNAi technology and has the characteristics of being prepared in large quantities and chemically modified. However, siRNA is susceptible to degradation in vivo. The effect of siRNA therapy alone is not ideal, so siRNA and anticancer drugs are administered in combination to reverse the MDR of tumors. Non-viral vectors are now commonly used to deliver siRNA and anticancer drugs to tumor sites. This article will review the progress of siRNA and chemotherapeutic drug delivery systems and their mechanisms for reversing multidrug resistance.

Nosocomial pneumonia is defined as pneumonia occurring ≥ 48 h after hospital admission in a patient without severe immunosuppression. It can occur in spontaneously breathing patients or with noninvasive ventilation (NIV) and mechanically ventilated patients. In patients with suspected ventilator-associated pneumonia (VAP) (semi)quantitative cultures of tracheobronchial aspirates or bronchoalveolar lavage fluid should be perfomed. The initial empirical antimicrobial treatment is determined by the risk for multidrug-resistant pathogens (MDRP). The advantage of combination treatment increases with the prevalence of MDRPs. The antibiotic treatment should be adapted when the microbiological results are available. After 72 h a standardized re-evaluation including the response to treatment and also checking of the suspected diagnosis of pneumonia in a structured form is mandatory. Treatment failure can occur as a primary or secondary failure and in the case of primary progression necessitates another comprehensive diagnostic work-up before any further antibiotic treatment.
UNASSIGNED: Die nosokomiale Pneumonie ist definiert als eine Pneumonie, die ≥ 48 h nach Krankenhausaufnahme bei einem Patienten ohne schwere Immunsuppression auftritt. Sie kann spontan atmende bzw. nichtinvasiv sowie beatmete Patienten betreffen. Bei Verdacht auf eine VAP (ventilatorassoziierte Pneumonie) sollen (semi)quantitative Kulturen eines Tracheobronchialsekrets oder einer bronchoalveolären Lavageflüssigkeit gewonnen werden. Die initiale kalkulierte antimikrobielle Therapie richtet sich nach dem Risiko für multiresistente Erreger (MRE). Der Vorteil der Kombinationstherapie steigt mit der MRE-Prävalenz. Die initiale kalkulierte antimikrobielle Therapie sollte nach Vorliegen der mikrobiologischen Ergebnisse angepasst werden. Nach 72 h ist eine Reevaluation erforderlich, die sowohl das Therapieansprechen als auch die Überprüfung der Verdachtsdiagnose Pneumonie in strukturierter Form einschließt. Ein Therapieversagen kann primär oder sekundär auftreten und erfordert bei primärer Progression eine erneute umfassende Diagnostik vor jeglicher Antibiotikatherapie.

Multidrug resistance (MDR) remains the most difficult problem facing conventional chemotherapy for cancers. Astragalus membranaceus is a historically traditional Chinese medicine. One of its bioactive components, formononetin, exhibits antitumor effects on various cancers. However, the effects of formononetin on MDR cancers have not been evaluated. Therefore, we investigated the defense\'s effects of formononetin on MDR. We used rhodamine 123 and doxorubicin efflux assays to analyze the inhibition kinetics of P-glycoprotein (P-gp) mediated-efflux. Cell viability was detected by sulforhodamine B assay, and the synergistic effects of formononetin combined with chemotherapeutic agents were further calculated using CompuSyn software. Molecular docking was performed with iGEMDOCK. We discovered that formononetin considerably induced oxidative stress and the disruption of mitochondrial membrane potential in MDR cancer cells. Furthermore, formononetin inhibits the P-gp efflux function by ATPase stimulation and the uncompetitive inhibition of P-gp-mediated effluxes of rhodamine 123 and doxorubicin. The molecular docking model indicates that formononetin may bind to P-gp by strong hydrogen bonds at Arginine (Arg) 489 and Glutamine (Gln) 912. Formononetin exhibits significant synergistic effects with vincristine and doxorubicin toward MDR cancer cells, and it synergistically suppressed tumor growth in vivo with paclitaxel. These results suggest that formononetin should be seen as a potential candidate for the adjuvant therapy of MDR cancers.

Multidrug resistance is a serious problem in modern medicine and the reason for the failure of various therapies. A particularly important problem is the occurrence of multidrug resistance in cancer therapies which affects many cancer patients. Observations on the effect of metformin-a well-known hypoglycemic drug used in the treatment of type 2 diabetes-on cancer cells indicate the possibility of an interaction of this substance with drugs already used and, as a result, an increase in the sensitivity of cancer cells to cytostatics. The aim of this study was to evaluate the effect of metformin on the occurrence of multidrug resistance of breast cancer cells. The MCF-7-sensitive cell line and the MCF-7/DX cytostatic-resistant cell line were used for this study. WST-1 and LDH assays were used to evaluate the effects of metformin and doxorubicin on cell proliferation and viability. The effect of metformin on increasing the sensitivity of MCF-7 and MCF-7/DX cells to doxorubicin was evaluated in an MDR test. The participation of metformin in increasing the sensitivity of resistant cells to the effect of the cytostatic (doxorubicin) has been demonstrated.

End-stage liver disease is a life-threatening clinical syndrome combined with a state of immune dysfunction. In this constellation patients are prone to bacterial, fungal and viral infections associated with markedly increased morbidity and mortality rates. Bacterial infections are the most prevalent kind of infection in patients with end-stage liver disease accounting for nearly 30%. The evolving rates of multidrug resistant organisms present enormous challenges in treatment strategies. Therefore, the urgent needs for prevention, early detection strategies and widespread treatment options are a necessity to handle the rising incidence of infection complications in end-stage liver disease.
UNASSIGNED: Die Leberzirrhose im Endstadium ist ein lebensbedrohliches klinisches Syndrom, das mit Funktionsstörungen des Immunsystems einhergeht. In dieser Lage neigen Patienten zu Infektionen mit bakteriellen, pilzlichen und viralen Erregern, assoziiert mit einer deutlich erhöhten Morbidität und Mortalität. Am häufigsten sind bei Patienten mit Leberzirrhose im Endstadium bakterielle Infektionen; sie machen einen Anteil von fast 30 % aus. Die wachsende Verbreitung multiresistenter Erreger stellt hinsichtlich der Behandlungsstrategien eine enorme Herausforderung dar. Daher besteht ein dringender Bedarf an Präventionsmaßnahmen, Früherkennungsstrategien und breit verfügbaren Therapieoptionen. All diese Ansätze sind erforderlich, wenn die steigende Inzidenz infektionsassoziierter Komplikationen bei Leberzirrhose im Endstadium bewältigt werden soll.

Multidrug resistance (MDR) of human tumors has resulted in an immediate need to develop appropriate new drugs. This work outlines the development of 20 potent IQQ N-oxide derivatives in two isomeric families, both exhibiting nanomolar GI50 against human tumor cell lines. Preliminary NCI-60 tumor screening sees the C(6) isomers achieve a mean GI50 > 2 times lower than the corresponding C(7) isomers. MDR evaluation of nine selected compounds reveals that each presents lower GI50 concentrations in two MDR tumor cell lines. Four of the series display nanomolar GI50 values against MDR cells, having selectivity ratios up to 2.7 versus the sensitive (parental) cells. The most potent compound 25 inhibits the activity of drug efflux pumps in MDR cells, causes significant ROS accumulation, and potently inhibits cell proliferation, causing alterations in the cell cycle profile. Our findings are confirmed by 3D spheroid models, providing new candidates for studies against MDR cancers.