Use of quercetin in animal feed : effects on the P-gp expression and pharmacokinetics of orally administrated enrofloxacin in chicken

Modulation of P-glycoprotein (P-gp, encoded by Mdr1) by xenobiotics plays central role in pharmacokinetics of various drugs. Quercetin has a potential to modulate P-gp in rodents, however, its effects on P-gp modulation in chicken are still unclear. Herein, study reports role of quercetin in modulation of P-gp expression and subsequent effects on the pharmacokinetics of enrofloxacin in broilers. Results show that P-gp expression was increased in a dose-dependent manner following exposure to quercetin in Caco-2 cells and tissues of chicken. Absorption rate constant and apparent permeability coefficient of rhodamine 123 were decreased, reflecting efflux function of P-gp in chicken intestine increased by quercetin. Quercetin altered pharmacokinetic of enrofloxacin by decreasing area under curve, peak concentration, and time to reach peak concentration and by increasing clearance rate. Molecular docking shows quercetin can form favorable interactions with binding pocket of chicken xenobiotic receptor (CXR). Results provide convincing evidence that quercetin induced P-gp expression in tissues by possible interaction with CXR, and consequently reducing bioavailability of orally administered enrofloxacin through restricting its intestinal absorption and liver/kidney clearance in broilers. The results can be further extended to guide reasonable use of quercetin to avoid drug-feed interaction occurred with co-administered enrofloxacin or other similar antimicrobials.Peer reviewedFinal Published versio

Efekt antynowotworowy inhibitora szlaku syntezy cholesterolu – lowastatyny i terapii fotodynamicznej w raku jelita grubego in vitro

Photodynamic therapy (PDT) is a promising treatment method for non-oncological and oncological diseases. PDT requires the use of photosensitizer, light, and cell oxygen. A selective, cytotoxic effects can be achieved in cancer cells, thanks to formation of radical oxygen species (ROS). Recent data indicate, that PDT with aminolevulinic acid (ALA) is successful in treatment of colorectal cancer. However, anti-cancer effects PDT in vivo, can vary in PDT in vitro, due to low level of oxygenation of tumor cells. Experimental research confirms the role of cholesterol in oncogenesis and indicates, that in colorectal cancer the cholesterol synthesis is disrupted; among others lovastatin belong to inhibitors 3-hydroxy-3-methyl-glutharyl-coenzyme A (HMG-CoA) enzyme of cholesterol synthesis pathway. Anti-tumor potential of statins: antiproliferative and pro-apoptotic, were demonstrated in various tumors in vitro and in vivo. Colorectal cancer, which often has genes mutations that are related to programmed death cells, shows resistance to chemotherapy. The objective of the research was to investigate the effect of antiproliferative and cytotoxic lovastatin and ALA-PDT (in low dose) working separately and in combination method (lovastatin and PDT) − for apoptosis induction, in metastatic colon cell line SW620. Our finding showed, that lovastatin inhibits the growth of cancer cells, depending on the dose and incubation time. ALA-PDT in low dose works on cell cytotoxic, yet do not initiate apoptosis. Whereas, preincubation of cells with lovastatin (IC50) increases the cytotoxic effect after PDT and induces apoptosis in cancer cells SW620, as demonstrated using an assay of Annexin V for flow cytometry. Our research demonstrates for the first time, the effectiveness of ALA-PDT connection with an inhibitor of cholesterol synthesis pathway – lovastatin, in increasing the cytotoxicity and induction of apoptosis in colon cancer cells, that are resistant to chemotherapy.Terapia fotodynamiczna (ang. photodynamic therapy, PDT) jest obiecującą metodą w leczeniu nowotworowych i nienowotworowych schorzeń. Działanie PDT wymaga użycia fotouczulacza, światła i tlenu komórkowego, dla uzyskania wybiórczego cytotoksycznego efektu w komórkach patologicznych. Efekt ten jest wynikiem powstania wolnych rodników (ROS). Badania pokazują, że PDT z kwasem aminolewulinowym (ALA) jest skuteczna w leczeniu raka jelita grubego. Jednak efekty PDT in vivo, ze względu na niski poziom oksygenacji guza, mogą odbiegać od działania PDT in vitro. Dane eksperymentalne potwierdzają rolę cholesterolu w procesie onkogenezy i wskazują na zaburzony szlak syntezy cholesterolu, m.in. w raku jelita grubego. Statyny, np. lowastatyna, należą do inhibitorów 3-hydroksy-3-metylo-glutarylo-koenzymu A (HMG-CoA) − enzymu szlaku syntezy cholesterolu. Potencjał antynowotworowy statyn, antyproliferacyjny i proapoptotyczny, wykazano w nowotworach in vitro i in vivo. Rak jelita grubego, cechujący się mutacjami genów związanych z apoptozą, wykazuje oporność na standardowe chemioterapeutyki. Celem pracy było zbadanie efektu antyproliferacyjnego i cytotoksycznego lowastatyny i ALA-PDT (w niskiej dawce) działających osobno, oraz w metodzie połączonej (lowastatyna i PDT) – na indukcję apoptozy w przerzutowej linii raka jelita grubego SW620. Wyniki pokazały, że lowastatyna hamuje wzrost komórek w związku zależnym od dawki i czasu inkubacji. ALA-PDT w niskiej dawce działa cytotoksycznie, ale nie inicjuje apoptozy. Natomiast preinkubacja komórek raka z lowastatyną (IC50) zwiększa efekt cytotoksyczny po PDT i indukuje apoptozę w komórkach, co wykazano w teście z aneksyną V na cytometrze przepływowym. Nasze wyniki po raz pierwszy demonstrują skuteczność metody łączonej: ALA-PDT i inhibitora syntezy szlaku cholesterolu – lowastatyny, w zwiększeniu cytotoksyczności i indukcji apoptozy w komórkach raka jelita grubego, opornego na chemioterapię

Optimization of the Load Capacity System of Powered Roof Support: A Review

Powered roof support is equipped with a hydraulic control system to ensure its required load capacity. The main problem arising from powered roof support during exploitation is providing the necessary load capacity. A decrease in load capacity is mainly associated with internal and external leakage in the cylinders, mainly in the hydraulic props. The hydraulic prop’s role is to ensure stability for the powered roof support. A special double block with an additional pressure boost was developed to counter the props’ leakage phenomenon. Pressure loss is replenished based on the solution proposed here. For this purpose, bench tests were commenced, in which a prop with an internal leakage was used. The research included the analysis of the operation of a boosted double block. The results allowed us to assess whether the developed solution can be the subject of further research conducted in real conditions

Minimizing Internal Leaks of a Powered Roof Support’s Hydraulic Prop Based on Double Block with Charging

The hydraulic system of a powered roof support performs two functions. The first function is to control the powered roof support in the extraction wall. The second function is to protect against adverse overloads resulting from rock mass pressing directly on the powered roof support. This damaging phenomenon is prevented by the protection of the powered roof support, with a safety valve built into the hydraulic system or directly into the prop. However, the third function proposed by the authors based on the research results is to minimize leaks. These leaks usually develop in the props or in the hydraulic system. The authors propose implementing changes to the hydraulic system for this purpose. The change consists of replacing the existing support block with a double block with charging. Tests were carried out in real conditions, that is, a mining wall. Tests in the mining wall were carried out on the powered roof support’s leaking prop. As a result of charging, the actual load capacity of the prop increased by about 10–50% in relation to the load capacity before charging. The use of a double block with charging ensured that the pressure in the under-piston space of the prop was maintained at a minimum of 250 bar. The results allowed us to determine the usefulness of the proposed solution and eliminate its disadvantages—the designated direction of research and development on the powered roof support allowed us to expand its functionality by minimizing leaks

Acellular pertussis vaccination facilitates Bordetella parapertussis infection in a rodent model of bordetellosis

Despite over 50 years of population-wide vaccination, whooping cough incidence is on the rise. Although Bordetella pertussis is considered the main causative agent of whooping cough in humans, Bordetella parapertussis infections are not uncommon. The widely used acellular whooping cough vaccines (aP) are comprised solely of B. pertussis antigens that hold little or no efficacy against B. parapertussis. Here, we ask how aP vaccination affects competitive interactions between Bordetella species within co-infected rodent hosts and thus the aP-driven strength and direction of in-host selection. We show that aP vaccination helped clear B. pertussis but resulted in an approximately 40-fold increase in B. parapertussis lung colony-forming units (CFUs). Such vaccine-mediated facilitation of B. parapertussis did not arise as a result of competitive release; B. parapertussis CFUs were higher in aP-relative to sham-vaccinated hosts regardless of whether infections were single or mixed. Further, we show that aP vaccination impedes host immunity against B. parapertussis—measured as reduced lung inflammatory and neutrophil responses. Thus, we conclude that aP vaccination interferes with the optimal clearance of B. parapertussis and enhances the performance of this pathogen. Our data raise the possibility that widespread aP vaccination can create hosts more susceptible to B. parapertussis infection

Phototherapy‐induced elevation of serum level of melanoma inhibitory activity

Background Phototherapy is a frequently used treatment modality for a variety of dermatologic diseases. UV radiation has different effects on the skin, for example increased production and release of cytokines and other proteins, and is involved in the initiation and progression of skin cancer. Objective of this clinical trial was to investigate potential systemic effects of UV phototherapy on cytokine profiles in blood. Methods In a prospective, mono-centric, one-armed study, the serum levels of the melanoma tumour marker "melanoma inhibitory activity" (MIA), Il-1 alpha, Il-4, Il-6, Il-10, TNF-alpha and IFN-gamma of 115 patients with different skin diseases were compared before and 24-48 hours as well as 2-4 weeks after the first phototherapy with PUVA (psoralen and ultraviolet A), UVA or UVB, or both. Data were analysed using linear mixed models. Results Estimated marginal means of MIA levels were 6.05 ng/mL (95%-CI: 5.37-6.72, range: 2.83-14.49) before the first treatment, which had significantly increased to 6.79 ng/mL 2-4 weeks after the first phototherapy (CI 95%: 6.12-7.47, range: 3.09-15.45; P = 0.0042). MIA levels 2-4 weeks after the first phototherapy were significantly higher than 24-48 hours after the first phototherapy (P = 0.0083). 2-4 weeks after the first treatment, TNF-alpha levels had decreased significantly (P = 0.033) more in patients with psoriasis who had responded well to phototherapy than in patients unresponsive to treatment. Serum levels of the other cytokines had not changed significantly. Conclusions Short-term phototherapy significantly increased the serum levels of the melanoma tumour marker MIA. The potential clinical relevance of these findings (ie an increased risk of melanoma) is unclear and should be further investigated