Diarrheal Diseases: A Review on Gastroenteritis Bacteria Global Burden and Alternative Control of Multidrug-Resistant Strains

Diarrheal diseases represent a significant and pervasive health challenge for humanity. The aetiology of diarrheal diseases is typically associated with the presence of enteropathogens, including viruses, bacteria and parasites. The implementation of preventive measures, including the maintenance of good food hygiene, effective water sanitation, and the development of rotavirus vaccines, has resulted in a notable reduction in the prevalence of the disease. However, the emergence of bacterial multidrug resistance due to the past or present inappropriate use of antibiotics has rendered bacterial infections a significant challenge. The objective of this review is threefold: firstly, to provide an overview of diarrheal diseases associated with bacteria;secondly, to offer a concise analysis of bacterial multidrug resistance on a global scale;and thirdly, to present the potential of filamentous fungi as an alternative solution to the challenge posed by multidrug-resistant strains. Campylobacter spp. is the most dangerous bacteria, followed by Shigella spp. and Vibrio cholerae in all age groups combined. However, Shigella spp. was the deadliest in children under five years of age and, together with E. coli, are the most antibiotic-resistant bacteria. With their highly developed secondary metabolism, fungi are a reservoir of natural bioactive compounds.

Efficacy and Safety of Combined Bedaquiline and Delamanid Use among Patients with Multidrug-Resistant Tuberculosis in Beijing,China

Objectives The combined use of bedaquiline and delamanid(BDQ-DLM)is limited by an increased risk of prolonging the QTc interval.We retrospectively evaluated patients who received DLM/BDQcontaining regimens at a TB-specialized hospital.We aimed to present clinical efficacy and safety data for Chinese patients.Methods This case-control study included patients with multidrug-resistant tuberculosis(MDR-TB)treated with BDQ alone or BDQ plus DLM.Results A total of 96 patients were included in this analysis:64 in the BDQ group and 32 in the BDQ+DLM group.Among the 96 patients with positive sputum culture at the initiation of BDQ alone or BDQ combined with DLM,46 patients(71.9%)in the BDQ group and 29(90.6%)in the BDQ-DLM group achieved sputum culture conversion during treatment.The rate of sputum culture conversion did not differ between the two groups.The time to sputum culture conversion was significantly shorter in the BDQ-DLM group than in the BDQ group.The most frequent adverse event was QTc interval prolongation;however,the frequency of adverse events did not differ between the groups.Conclusion In conclusion,our results demonstrate that the combined use of BDQ and DLM is efficacious and tolerable in Chinese patients infected with MDR-TB.Patients in the BDQ-DLM group achieved sputum culture conversion sooner than those in the BDQ group.

Apatinib reduces liver cancer cell multidrug resistance by modulating NF-κB signaling pathway

Objectives:This investigation aimed to elucidate the inhibitory impact of apatinib on the multidrug resistance of liver cancer both in vivo and in vitro.Methods:To establish a Hep3B/5-Fu resistant cell line,5-Fu concentrations were gradually increased in the culture media.Hep3B/5-Fu cells drug resistance and its alleviation by apatinib were confirmed via flow cytometry and Cell Counting Kit 8(CCK8)test.Further,Nuclear factor kappa B(NF-κB)siRNA was transfected into Hep3B/5-Fu cells to assess alterations in the expression of multidrug resistance(MDR)-related genes and proteins.Nude mice were injected with Hep3B/5-Fu cells to establish subcutaneous xenograft tumors and then categorized into 8 treatment groups.The treatments included oxaliplatin,5-Fu,and apatinib.In the tumor tissues,the expression of MDRrelated genes was elucidated via qRT-PCR,immunohistochemistry,and Western blot analyses.Results:The apatinibtreated mice indicated slower tumor growth with smaller size compared to the control group.Both the in vivo and in vitro investigations revealed that the apatinib-treated groups had reduced expression of MDR genes GST-pi,LRP,MDR1,and p-p65.Conclusions:Apatinib effectively suppresses MDR in human hepatic cancer cells by modulating the expression of genes related to MDR,potentially by suppressing the NF-κB signaling pathway.

Identification of FDA-Approved Drugs as Modulators of Multidrug Resistance Protein 2 (MRP2/ABCC2) Expression Levels in MRP2-Overexpressing Cells: Preliminary Data

Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have shown that MRP2 can significantly affect the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of many therapeutic drugs and chemicals found in the environment and diet. This transporter can also efflux newly developed anticancer agents that target specific signaling pathways and are major clinical markers associated with multidrug resistance (MDR) of several types of cancers. MDR remains a major limitation to the advancement of the combinatorial chemotherapy regimen in cancer treatment. In addition to anticancer agents, MRP2 reduces the efficacy of various drug classes such as antivirals, antimalarials, and antibiotics. The unique role of MRP2 and its contribution to MDR makes it essential to profile drug-transporter interactions for all new and promising drugs. Thus, this current research seeks to identify modulators of MRP2 protein expression levels using cell-based assays. A unique recently approved FDA library (372 drugs) was screened using a high-throughput In-Cell ELISA assay to determine the effect of these therapeutic agents on protein expression levels of MRP2. A total of 49 FDA drugs altered MRP2 protein expression levels by more than 50% representing 13.17% of the compounds screened. Among the identified hits, thirty-nine (39) drugs increased protein expression levels whereas 10 drugs lowered protein expression levels of MRP2 after drug treatment. Our findings from this initial drug screening showed that modulators of MRP2 peregrinate multiple drug families and signify the importance of profiling drug interactions with this transporter. Data from this study provides essential information to improve combinatorial drug therapy and precision medicine as well as reduce the drug toxicity of various cancer chemotherapies.

Multidrug-Resistant of Escherichia coli and Salmonella spp. Strains in Chicken Feces Intended for Consumption in Open Spaces of Ouagadougou, Burkina Faso

Resistant bacteria can be transmitted to humans through feces or contaminated meat from local chickens. Bacterial strains were isolated from the intestinal contents of 400 local chicken samples from various sales sites. These strains were then characterized using bacteriological and biochemical methods to identify resistant strains. In a study conducted in Ouagadougou, we systematically collected chicken fecal samples from 20 locations across the city, followed by isolation and identification of Salmonella spp. using specific enrichment and culture methods, as well as Escherichia coli. Bacterial strains were characterized using antibiotic resistance profiles were determined through agar diffusion tests, revealing sensitivity or resistance to a range of antibiotics based on established scientific criteria. The results showed that out of the 400 samples collected, 81.25% and 63.5% were contaminated by Escherichia coli and Salmonella spp., respectively. Among these, 86.15% of identified Escherichia coli and 50.78% of Salmonella spp. displayed resistance to at least one tested antibiotic. Among 280 Escherichia coli isolates identified resistant to at least one antibiotic, 31.07% were resistant to cefotaxime (CTX), 20.35% to ceftazidime (CAZ), 21.07% to ceftriaxone (CTR), 75% to amoxicillin clavulanic acid (AMC), 23.57% aztreoname (ATM) and 27.14% were resistant to imipenem (IMP). In the case of the 129 Salmonella spp. isolates resistant to at least one tested antibiotic, 34.88% were resistant to CTX;41.08% to CAZ;35.65% to CTR, 92% to AMC, 39.53% to ATM and finally 47.28% were resistant to IMP. Our study revealed high prevalence of resistance in bacterial strains isolated from local chickens sold outdoors in Ouagadougou. These findings raise significant public health concerns, due to the possible transmission of these resistant strains to humans through the consumption of contaminated meat, thus complicating the treatment of bacterial infections.

Survey of Multidrug Resistance and Class I Integron Prevalence in Chicken-derived Salmonella

[Objective] This study aimed to investigate the multidrug resistance and prevalence of class I integrons in Salmonel a. [Method] Salmonel a strains were isolated from chicken farms in Shandong Province. Kauffmann-White classification method was employed to analyze the serotypes of Salmonel a strains. Minimum in-hibition concentration （MIC） of Salmonel a strains against 19 common antimicrobial drugs was analyzed determined with microdilution method. The class I integrons and carried drug resistance gene cassettes were detected by PCR. [Result] A total of 311 Salmonel a strains were isolated and classified into two serotypes, including 133 Salmonel a Indiana strains and 178 Salmonel a Enteritidis strains. Drug sensitivity test showed that the isolated Salmonel a strains were general y resistant to sulfadiazine, sulfamethoxazole, nalidixic acid, ampicil in, tetracycline, doxycycline and trimethoprim, with a multidrug resistance rate of 91.0% （283/311）; 99% strains were sensitive to amikacin and colistin. PCR assay indicated that the detection rate of class I integrons was 65.0% （202/311）; the positive rate of class I integrons in Salmonel a strains with multidrug resistance was 92.6%; among 202 positive strains, six strains carried gene cassette dfr17-aadA5. [Conclusion] According to the above results, class I integrons exist general y in Salmonel a and are closely associated with the multidrug resistance of Salmonel a strains.

Structure-activity Relationship of Phenothiazines for Inhibition of Protein Kinase C and Reversal of Multidrug Resistance

Studies on structure-activity relationship of phenothiazines (PTZs) forinhibition of protein kinase C (PKC) and reversal of multidrug resistance (MDR) has been made invitro. The results showed that the order of potency of reversal effect of PTZs on MDR is as follows:2-COC_3 H_7 > 2-CF_3 > 2-COCH_3 > H. The type of piperazinyl substitution also significantlyaffected potency against MDR. The results show the order: CH_3 > COOC_2 H_5 > C_2 H_4 OH. Inaddition, PKC plays a marked role in diverse cellular process including MDR. Some derivatives of PTZwas tested for inhibition of PKC, of which PTZ11 showed the highest inhibitory effect of MDR andPKC, implying a potential reversal agent of MDR for tumor therapy in the future. We also tried toexplore the possible binding model of PTZs to PKC. Our molecular-modeling study preliminarilysuggests how these PTZs bind to PKC and provides a structural basis for the design of high affinityPKC-modulator. The infor-mation may be used in the rational design of more effective drugs.

Reversal of Multidrug Resistance by Neferine in Adriamycin Resistant Human Breast Cancer Cell Line MCF-7/ADM

Objective: To study the reversal effect of neferine on adriamycin (ADM) resistant human breast cancer cell line MCF-7/ADM. Methods: The cytotoxic effect of Nef or ADM was determined by 3-[4, 5-dimethylthiazol-2.-yl], 5-diphenyl tetraxolium bromid (MTT) assay. Apoptosis and the expression of P-glycoprotein (P-gp) were detected by flow cytometry (FCM). The intracellular ADM concentration was measured by HPLC. Results: Nef at 1, 5, 10 mol/L decreased the IC50 of ADM to MCF-7/ADM from 11.63 g/mL to 4.59, 2.44, 0.27 g/mL respectively. MCF-7/ADM could resist the apoptosis induced by ADM while Nef (1-10 mol/L) could augment ADR-mediated apoptosis. Nef (10 mol/L) increased the accumulation of ADM up to 2.88 fold in MCF-7/ADM but not in sensitive cells MCF-7/S and reduced the expression of P-gp in MCF-7/ADM cells. Conclusion: Nef can circumvent multidrug resistance (MDR) of MCF-7/ADM cells and the mechanism was associated with the increase of intracellular accumulation of ADM and the reduced expression of P-gp in MCF-7/ADM cells.

Using ^(99m)Tc-MIBI to Evaluate the Effects of Chemosensitizer on P-glycoprotein in Multidrug-resistant Carcinoma Cells

To establish a method to evaluate the effects of chemosensitizer onP-glycoprotein using ^(99m)Tc-MIBI, and observe the changes of ^(99m)Tc-MIBI uptake kinetics andP-glycoprotein levels after using verapamil in MDR human breast cells MCF-7/Adr. Methods: MDR breastcarcinoma cells, MCF-7/Adr, were incubated and different protocols were performed. Protocol Ⅰ: achemosensitizer, verapamil (10 μmol/L), was added into cell culture medium, while in control group,the same volume of DMEM was given. Cells were harvested after 2 h incubation with ^(99m)Tc-MIBI.Protocol Ⅱ: Verapamil (10 μmol/L) was added into cell culture medium and incubated for 20 min, 40min, 60 min, 80 min, 8 h, 24 h, 48 h and 72 h respectively. Cells were harvested after 2 hincubation with ^(99m)Tc-MIBI. The radioactivity of the cells was measured and P-glycoproteinexpression levels were determined with immunohistochemical stain. Results: Protocol Ⅰ: After 2hincubation with verapamil the cellular uptake of ^(99m)Tc-MIBI was remarkably higher than controlgroup (t=2.33, P 【 0.05), but there was no difference in P-glycoprotein expression levels betweentwo groups (P 】 0.05). Protocol Ⅱ: In verapamil group, ^(99m)Tc-MIBI uptake was increased withincubation time prolonging (F=58.2, P 【 0.05). When verapamil incubation time surpassed 8 h the^(99m)Tc-MIBI uptake negatively correlated to the P-glycoprotein expression levels (r=-0.73, P 【0.01). However, when incubation time was less than 80 min, there was no correlation between^(99m)Tc-MIBI accumulation and P-glycoprotein levels (r=0.16, P 】 0.05). Conclusion: ^(99m)Tc-MIBImay be used to evaluate the qualitative as well as quantitative change of P-glycoprotein expressionlevels induced by the chemosensitizer, verapamil.

The Activity of Erianin and Chrysotoxine from Dendrobium chrysotoxum to Reverse Multidrug Resistance in B16/h MDR-1 Cells

The ability of two dihydrostilbene derivatives erianin and chrysotoxine from Dendrobium chrysotoxum to reverse multidrug resistant (MDR) cells was investigated using murine B16 melanoma cells transfected with the human MDR 1 gene and crossresistant to vinblastine and adriamycin (B16/h MDR 1 cells). Both of the two compounds were shown to increase the accumulation of adriamycin, the P glycoprotein (P gp) substrate, in B16/h MDR 1 transfectants.

Influence of efflux pump inhibitors on the multidrug resistance of Helicobacter pylori

AIM:To evaluate the effect of efflux pump inhibitors (EPIs) on multidrug resistance of Helicobacter pylori (H. pylori).METHODS: H. pylori strains were isolated and cultured on Brucella agar plates with 10% sheep's blood. The multidrug resistant (MDR) H. pylori were obtained with the inducer chloramphenicol by repeated doubling of the concentration until no colony was seen, then the susceptibilities of the MDR strains and their parents to 9 antibiotics were assessed with agar dilution tests. The present study included periods before and after the advent of the EPIs, carbonyl cyanide m-chlorophenyl hydrazone (CCCP), reserpine and pantoprazole), and the minimum inhibitory concentrations (MICs) were determined accordingly. In the same way, the effects of 5 proton pump inhibitors (PPIs), used in treatment of H. pylori infection, on MICs of antibiotics were evaluated.RESULTS: Four strains of MDR H. pylori were induced successfully, and the antibiotic susceptibilities of MDR strains were partly restored by CCCP and pantoprazole, but there was little effect of reserpine. Rabeprazole was the most effective of the 5 PPIs which could decrease the MICs of antibiotics for MDR H. pylori significantly.CONCLUSION: In vitro, some EPIs can strengthen the activities of different antibiotics which are the putative substrates of the efflux pump system in H. pylori.

Inhibitory effects of emodin, baicalin, schizandrin and berberine on hef A gene: Treatment of Helicobacter pylori-induced multidrug resistance

AIM: To investigate the inhibitory effects of emodin, baicalin, etc.on the hefA gene of multidrug resistance(MDR) in Helicobacter pylori(H.pylori).METHODS: The double dilution method was used to screen MDR H.pylori strains and determine the minimum inhibitory concentrations(MICs) of emodin, baicalin, schizandrin, berberine, clarithromycin, metronidazole, tetracycline, amoxicillin and levofloxacin against H.pylori strains.After the screened MDR stains were treated with emodin, baicalin, schizandrin or berberine at a 1/2 MIC concentration for 48 h, changes in MICs of amoxicillin, tetracycline, levofloxacin, metronidazole and clarithromycin were determined.MDR strains with reduced MICs of amoxicillin were selected to detect the hefA mR NA expression by realtime quantitative PCR.RESULTS: A total of four MDR H.pylori strains were screened.Treatment with emodin, baicalin, schizandrin and berberine significantly decreased the MICs of amoxicillin and tetracycline against some strains, decreased by 1 to 2 times, but did not significantly change the MICs of clarithromycin, levofloxacin, and metronidazole against MDR strains.In the majority of strains with reduced MICs of amoxicillin, hef A m RNA expression was decreased; one-way ANOVA(SPSS 12.0) used for comparative analysis, P < 0.05.CONCLUSION: Emodin, baicalin, schizandrin and berberine significantly decreased the MICs of amoxicillin and tetracycline against some H.pylori strains, possibly by mechanisms associated with decreasing hefA mR NA expression.

JNK1,JNK2,and JNK3 are involved in P-glycoprotein-mediated multidrug resistance of hepatocellular carcinoma cells

BACKGROUND:Multidrug resistance(MDR)is extremely common in hepatocellular carcinoma(HCC)and is a major problem in cancer eradication by limiting the efficacy of chemotherapy.Modulation of c-Jun NH2-terminal kinase(JNK)activation could be a new method to reverse MDR.However,the relationship between JNK activity and MDR in HCC cells is unknown.This study aimed to explore the relationship between MDR and JNK in HCC cell lines with different degrees of MDR.METHODS:A MDR human HCC cell line,SMMC-7721/ ADM,was developed by exposing parental cells to gradually increasing concentrations of adriamycin.The MTT assay was used to determine drug sensitivity.Flow cytometry was used to analyze the cell cycle distribution and to measure the expression levels of P-glycoprotein(P-gp)and MDR-related protein(MRP)-1 in these cells.JNK1,JNK2 and JNK3 mRNA expression levels were quantified by real-time PCR.Expression and phosphorylation of JNK1,JNK2,and JNK3 were analyzed by Western blotting.RESULTS:The MDR of SMMC-7721/ADM cells resistant to 0.05 mg/L adriamycin was mainly attributed to the overexpression of P-gp but not MRP1.In addition,these cells had a significant increase in percentage in the S phase,accompanied by a decrease in percentage in the G0/G1 phase,which is likely associated with a reduced ability for cell proliferation and MDR generation.We found that JNK1,JNK2,and JNK3 activities were negatively correlated with the degree of MDR in HCC cells.CONCLUSION:This study suggests that JNK1,JNK2,and JNK3 activities are negatively correlated with the degree of MDR in HCC cells.

Antimicrobial peptides: new hope in the war against multidrug resistance

The discovery of antibiotics marked a golden age in the revolution of human medicine. However,decades later, bacterial infections remain a global healthcare threat, and a return to the pre-antibiotic era seems inevitable if stringent measures are not adopted to curb the rapid emergence and spread of multidrug resistance and the indiscriminate use of antibiotics. In hospital settings, multidrug resistant(MDR) pathogens, including carbapenem-resistant Pseudomonas aeruginosa, vancomycin-resistant enterococci(VRE), methicillin-resistant Staphylococcus aureus(MRSA), and extendedspectrum β-lactamases(ESBL) bearing Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae are amongst the most problematic due to the paucity of treatment options,increased hospital stay, and exorbitant medical costs. Antimicrobial peptides(AMPs) provide an excellent potential strategy for combating these threats. Compared to empirical antibiotics, they show low tendency to select for resistance, rapid killing action, broad-spectrum activity, and extraordinary clinical efficacy against several MDR strains. Therefore, this review highlights multidrug resistance among nosocomial bacterial pathogens and its implications and reiterates the importance of AMPs as next-generation antibiotics for combating MDR superbugs.

Biofilm formation in clinical isolates of nosocomial Acinetobacter baumannii and its relationship with multidrug resistance

Objective: To check biofilm formation by Acinetobacter baumannii(A. baumannii)clinical isolates and show their susceptibility to different antibiotics and investigate a possible link between establishment of biofilm and multidrug resistance.Methods: This study was performed on clinical samples collected from patients with nosocomial infections in three hospitals of Tehran. Samples were initially screened by culture and biochemical tests for the presence of different species of Acinetobacter. Identifications were further confirmed by PCR assays. Their susceptibilities to 11 antibiotics of different classes were determined by disc diffusion method according to Clinical and Laboratory Standards Institute guidelines. The ability to produce biofilm was investigated using methods: culture on Congo red agar, microtiter plate, and test tube method.Results: From the overall clinical samples, 156 specimens were confirmed to contain A. baumannii. The bacteria were highly resistant to most antibiotics except polymyxin B.Of these isolates, 10.26% were able to produce biofilms as shown on Congo red agar.However, the percentage of bacteria with positive biofilm in test tube, standard microtiter plate, and modified microtiter plate assays were 48.72%, 66.66%, and 73.72%, respectively. At least 92% of the biofilm forming isolates were multidrug resistant.Conclusions: Since most of the multidrug resistant strains produce biofilm, it seems necessary to provide continuous monitoring and determination of antibiotic susceptibility of clinical A. baumannii. This would help to select the most appropriate antibiotic for treatment.

Multidrug-resistant bacterial infections after liver transplantation: An ever-growing challenge

Bacterial infections are a leading cause of morbidity and mortality among solid organ transplant recipients.Over the last two decades,various multidrug-resistant(MDR)pathogens have emerged as relevant causes of infection in this population.Although this fact reflects the spread of MDR pathogens in health care facilities worldwide,several factors relating to the care of transplant donor candidates and recipients render these patients particularly prone to the acquisition of MDR bacteria and increase the likelihood of MDR infectious outbreaks in transplant units.The awareness of this high vulnerability of transplant recipients to infection leads to the more frequent use of broad-spectrum empiric antibiotic therapy,which further contributes to the selection of drug resistance.This vicious cycle is difficult to avoid and leads to a scenario of increased complexity and narrowed therapeutic options.Infection by MDR pathogens is more frequently associated with a failure to start appropriate empiric antimicrobial ther-apy.The lack of appropriate treatment may contribute to the high mortality occurring in transplant recipients with MDR infections.Furthermore,high therapeutic failure rates have been observed in patients infected with extensively-resistant pathogens,such as carbapenemresistant Enterobacteriaceae,for which optimal treatment remains undefined.In such a context,the careful implementation of preventive strategies is of utmost importance to minimize the negative impact that MDR infections may have on the outcome of liver transplant recipients.This article reviews the current literature regarding the incidence and outcome of MDR infections in liver transplant recipients,and summarizes current preventive and therapeutic recommendations.

Establishment of a human hepatoma multidrug resistant cell line in vitro

AIM:To establish a multidrug-resistant hepatoma cell line(SK-Hep-1),and to investigate its biological characteristics.METHODS:A highly invasive SK-Hep-1 cell line of human hepatocellular carcinoma,also known as malignant hepatoma was incubated with a high concentration of cisplatin(CDDP) to establish a CDDP-resistant cell subline(SK-Hep-1/CDDP).The 50% inhibitory dose(IC50) values and the resistance indexes [(IC50 SK-Hep-1/CDDP)/(IC50 SK-Hep-1)] for other chemotherapeutic agents and the growth curve of cells were all evaluated using cell counting kit-8 assays.The distribution of the cell cycles were detected by flow cytometry.Expression of acquired multidrug resistance P-glycoprotein(MDR1,ABCB1) and multidrug resistance-associated protein 1(MRP1,ABCC1) was compared with that in parent cells by Western blotting and immunofluorescence combined with laser scanning confocal microscopy.RESULTS:The SK-Hep-1/CDDP cells(IC50 = 70.61 ± 1.06 μg/mL) was 13.76 times more resistant to CDDP than the SK-Hep-1 cells(IC50 = 5.13 ± 0.09 μg/mL),and CDDP-resistant cells also demonstrated cross-resistance to many anti-tumor agents such as doxorubicin,5-fluorouracil and vincristine.Similar morphologies were determined in both SK-Hep-1 and SK-Hep-1/CDDP groups.The cell cycle distribution of the SK-Hep-1/CDDP cell line exhibited a significantly increased percentage of cells in S(42.2% ± 2.65% vs 27.91% ± 2.16%,P < 0.01) and G2/M(20.67% ± 5.69% vs 12.14% ± 3.36%,P < 0.01) phases in comparison with SK-Hep-1 cells,while the percentage of cells in the G0/G1 phase decreased(37.5% ± 5.05% vs 59.83% ± 3.28%,P < 0.01).The levels of MDR1 and MRP1 were overexpressed in the SK-Hep-1/CDDP cells exhibiting the MDR phenotype.CONCLUSION:Multiple drug resistance of multiple drugs in the human hepatoma cell line SK-Hep-1/CDDP was closely related to the overexpression of MDR1 and MRP1.

Immune formulation-assisted conventional therapy on anti-infective effectness of multidrug-resistant Mycobacterium tuberculosis infection mice

Objective:To study the effect of immune formulation-assisted conventional therapy on antiinfective ability of multidrug-resistant Mycobacterium tuberculous infection mice.Methods:BALB/c mice were used as experimental animals,multidrug-resistant Mycobacterium tuberculosis infection models were built,randomly divided into model group,moxifloxacin group,thymopentin group and combined treatment group and given corresponding drug intervention,and then colony numbers in the spleen and lung,T lymphocyte subset contents and programmed death-1(PD-1) expression levels in peripheral blood were detected.Results:Colony numbers in lung and spleen of moxifloxacin group and thymopentin group were significantly lower than those of model group and colony numbers in lung and spleen of combined treatment group were significantly lower than those of moxifloxacin group and thymopentin group:contents of CD3^+CD4^+T cells,Thl and Thl7 in peripheral blood of moxifloxacin group and thymopentin group were higher than dtose of model group,and contents of CD3^+CD8^+T cells.Th2 and Treg were lower than those of model group;contents of CD3^+CD4^+T cells.Th 1 and Th 17 in peripheral blood of combined treatment group were higher than those of moxifloxacin group and thymopentin group,and contents of CD3^+CD8^+T cells.Th2 and Treg were lower than those of moxifloxacin group and thymopentin group:PD-I expression levels on T lymphocyte,B lymphocyte and monocyte surface in peripheral blood of moxifloxacin group and thymopentin group were lower than those of model group,and PD-I expression levels on T lymphocyte.B lymphocyte and monocyte surface in peripheral blood of combined treatment group were lower than those of moxifloxacin group and thymopentin group.Conclusions:Immune formulation thymopentin can enhance the anti-infective ability of multidrug-resistant Mycobacterium tuberculosis infection mice,decrease bacterial load in lung and spleen,and enhance immune function.

Nanotechnology-based combination therapy for overcoming multidrug-resistant cancer

Multidrug resistance(MDR) is a major obstacle to successful cancer treatment and is crucial to cancer metastasis and relapse.Combination therapy is an effective strategy for overcoming MDR. However, the different pharmacokinetic(PK) profiles of combined drugs often undermine the combination effect in vivo, especially when greatly different physicochemical properties(e.g.,those of macromolecules and small drugs) combine. To address this issue, nanotechnology-based codelivery techniques have been actively explored. They possess great advantages for tumor targeting, controlled drug release, and identical drug PK profiles. Thus,a powerful tool for combination therapy is provided, and the translation from in vitro to in vivo is facilitated. In this review, we present a summary of various combination strategies for overcoming MDR and the nanotechnology-based combination therapy.

Reversal of multidrug resistance of hepatocellular carcinoma cells by metformin through inhibiting NF-κB gene transcription

AIM: To interfere with the activation of nuclear factor-κB(NF-κB) with metformin and explore its effect in reversing multidrug resistance(MDR) of hepatocellular carcinoma(HCC) cells.METHODS: Expression of P-glycoprotein(P-gp) and NF-κB in human HepG 2 or HepG 2/adriamycin(ADM) cells treated with pC MV-NF-κB-small interference RNA(siR NA) with or without metformin, was analyzed by Western blot or fluorescence quantitative PCR. Cell viability was tested by CCK-8 assay. Cell cycle and apoptosis were measured by flow cytometry and Annexin-V-PE/7-AnnexinV apoptosis detection double staining assay, respectively. RESULTS: P-gp overexpression in HepG 2 and HepG 2/ADM cells was closely related to mdr1 mR NA(3.310 ± 0.154) and NF-κB mR NA(2.580 ± 0.040) expression. NF-κB gene transcription was inhibited by specific siR NA with significant down-regulation of P-gp and enhanced HCC cell chemosensitivity to doxorubicin. After pretreatment with metformin, Hep G2/ADM cells were sensitized to doxorubicin and P-gp was decreased through the NF-κB signaling pathway. The synergistic effect of metformin and NF-κB siR NA were found in HepG 2/ADM cells with regard to proliferation inhibition, cell cycle arrest and inducing cell apoptosis. CONCLUSION: Metformin via silencing NF-κB signaling could effectively reverse MDR of HCC cells by downregulating MDR1/P-gp expression.