Arsenic enhances cell death and DNA damage induced by ultraviolet B exposure in mouse epidermal cells through the production of reactive oxygen species

Summary

Background

Ultraviolet (UV)B radiation has long been considered a carcinogen in both epidemiological surveys and experimental studies. However, recent work has suggested that different dosages of UVB exert different influences on cells. There are also co‐carcinogenesis factors such as arsenic that affect the role of UVB.

Aim

To explore the co‐carcinogenesis effect of UVB and arsenic on the mouse epidermal cell line JB6 and the mechanism underlying it.

Methods

Growth of JB6 cells was measured by MTT assay. We carried out a comet assay to determine the DNA damage caused by UVB and arsenic, and tested the expression of DNA repair protein by western blotting. Reactive oxygen species (ROS) were measured using DCF and DHE staining, and changes in antioxidant enzymes were assessed using western blotting.

Results

Viability assays showed that arsenic increased the UVB‐induced death rate. Arsenic enhanced DNA damage caused by UVB both directly by injury to double‐stranded DNA and indirectly by reducing the capability of DNA repair in JB6 cells. All of these effects are the results of increased ROS generation and reduced expression of the antioxidant enzyme superoxide dismutase (SOD)1.

Conclusion

Arsenic was found to enhance UVB‐induced production of ROS and to downregulate SOD1 expression, leading to DNA damage and apoptosis in mouse skin cells. The combination of arsenic and UVB exposure was found to differentially regulate the expression of SOD1 and SOD2.

https://ift.tt/2PIxrdn

The role of therapeutic drug monitoring in treatment optimization in tuberculosis and diabetes mellitus co-morbidity [Letters]

With great interest we read the paper by Alfarisi et al reporting the effects of diabetes mellitus (DM) on the pharmacokinetics and pharmacodynamics of tuberculosis treatment (1)....

https://ift.tt/2OStg9i

Evaluation of carbapenems for multi/extensive-drug resistant Mycobacterium tuberculosis treatment [Pharmacology]

M/XDR-TB has become an increasing threat in high burden countries but also in affluent regions due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of M. tuberculosis. To better understand the potential of carbapenems for the treatment of M/XDR-TB, the aim of this review was to evaluate the literature on currently available in vitro, in vivo and clinical data on carbapenems in the treatment of M. tuberculosis and detection of knowledge gaps, in order to target future research.

In February 2018, a systematic literature search of PubMed and Web of Science was performed. Overall the results of the studies identified in this review, which used a variety of carbapenem susceptibility tests on clinical and lab strains of M. tuberculosis, are consistent. In vitro the activity of carbapenems against M. tuberculosis is increased when used in combination with clavulanate, a BLaC inhibitor. However, clavulanate is not commercially available alone, and therefore is it practically impossible to prescribe carbapenems in combination with clavulanate at this time. Few in vivo studies have been performed, one prospective, two observational and seven retrospective clinical studies to assess effectiveness, safety and tolerability of three different carbapenems (imipenem, meropenem and ertapenem). Presently we found no clear evidence to select one particular carbapenem among the different candidate compounds, to design an effective M/XDR-TB regimen. Therefore more clinical evidence and dose optimization substantiated by hollow fiber infection studies are needed to support repurposing carbapenems for the treatment of M/XDR-TB.

https://ift.tt/2zg3k2j

Inhibitors of Signaling Pathways that Block Reversal of HIV-1 Latency [Antiviral Agents]

Signaling pathways play a key role in HIV-1 latency. In this study, we used the 24ST1NLESG cell line of HIV-1 latency to screen a library of structurally diverse, medicinally active, cell permeable kinase inhibitors, which target a wide range of signaling pathways, to identify inhibitors of HIV-1 latency reversal. The screen was carried-out in the absence or presence of three mechanistically distinct latency reversing agents (LRAs), namely prostratin, panobinostat and JQ-1. We identified inhibitors that only blocked the activity of a specific LRA, as well as inhibitors that blocked the activity of all LRAs. For example, we identified 12 inhibitors targeted toward protein kinase C or downstream kinases that blocked the activity of prostratin. We also identified 12 kinase inhibitors that blocked reversal of HIV-1 latency irrespective of the LRA used in the screen. Of these danusertib, an Aurora kinase inhibitor, and PF-3758309, a PAK4 inhibitor, were the most potent. The 50% inhibitory concentrations in the 24ST1NLESG cells ranged from 40-147 nM for danusertib (selectivity indices >150) and from 0.1-1nM for PF-3758309 (selectivity indices >3,300). Both danusertib and PF-3758309 inhibited latency reversal in CD4+ T cells isolated from HIV-1-infected donors. Collectively, our study describes a chemical approach that can be applied to elucidate the role of signaling pathways involved in LRA activity, or the maintenance of HIV-1 latency; and also identifies inhibitors of latent HIV-1 reactivation that could be used with antiretroviral therapy to reduce residual viremia.

https://ift.tt/2OStfCg

Population Pharmacokinetics of Mefloquine Intermittent Preventive Treatment for Malaria in Pregnancy in Gabon [Pharmacology]

Introduction Mefloquine is evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first line drug sulfadoxine-pyrimethamine (SP). This study determined the pharmacokinetic characteristics of the mefloquine stereoisomers and its metabolite carboxymefloquine (CMQ) when given as IPTp in pregnant women. Also, the relationship between plasma concentrations of the three analytes and cord samples was evaluated and potential covariates influencing the pharmacokinetic properties were assessed.

Materials and Methods A population pharmacokinetic analysis was performed with 264 pregnant women of a randomized controlled trial evaluating a single and split-dose regimen of two 15 mg/kg mefloquine dosings at least one month separated versus SP-IPTp. Both mefloquine enantiomers and its carboxy-metabolite (CMQ), measured in plasma and cord, were applied for pharmacokinetic modelling using NONMEM 7.3.

Results Both enantiomers and CMQ were described simultaneously by two-compartment models. In the split-dose group the mefloquine bioavailability was significantly increased by 5%. CMQ induced its own metabolism significantly. Maternal and cord blood concentrations were significantly correlated (r²=0.84) at delivery. With the investigated dosing regimens prophylactic levels are not constantly achieved. A modelling tool for simulation of the pharmacokinetics of alternative mefloquine regimens is presented.

Discussion This first pharmacokinetic characterization of mefloquine IPTp indicates adequate exposure in both mefloquine regimens, however, concentrations at delivery were below previously suggested threshold levels. Our model can serve as valuable tool for researchers and clinicians to develop and optimise alternative dosing regimens for IPTp in pregnant women.

https://ift.tt/2zhpLo4

The Role of Rifampin against Staphylococcal Biofilm Infections in Vitro, in Animal Models, and in Orthopedic Device-Related Infections. [Minireviews]

Rifampin has been used as an agent in combination therapy in orthopedic device-related infections (ODRI) for almost three decades. The aim of this review is to provide data regarding the role of rifampin against biofilm infection in vitro, in animal models, and in clinical ODRI. Available data are gathered in order to present the rational use of rifampin combinations in patients with periprosthetic joint infection (PJI). In-vitro data, animal data and available clinical data in the field of staphylococcal PJI will be reviewed. The role of rifampin is well-defined in patients with PJI and is indicated in those who fulfill the Infectious Diseases Society of America criteria for debridement and implant retention or one-stage exchange. It should be used with care because of the danger of rapid emergence of resistance. Potential drug interactions should be considered.

https://ift.tt/2OSteyc

In-vivo gentamicin susceptibility test for prevention of bacterial biofilms in bone tissue and on implants [Susceptibility]

Objectives: To set up an in-vivo gentamicin susceptibility test for biofilm prevention in bone tissue and on implants.

Methods: Twenty-five pigs were allocated to six groups. Group A (n=6) was inoculated with saline. Groups B (n=6), C (n=3), D (n=3), E (n=3) and F (n=4) were inoculated with 10 μL saline containing 10⁴ CFU of Staphylococcus aureus. Different concentrations based on the minimal inhibitory concentrations (MIC) of gentamicin to the specific strain were added to the 10 μL inoculum of Groups C (160xMIC), D (1,600xMIC), E (16,000xMIC) and F (160,000xMIC). The inoculums were injected into a pre-drilled tibial implant cavity followed by insertion of a steel implant (2 x 15 mm). The pigs were euthanized after five days. In-vitro, all the used doses were found bacteriostatic after up to 6 hours.

Results: All implant cavities of pigs inoculated with bacteria and bacteria + 160xMIC or 1,600xMIC were positive for S. aureus. In each of the Groups E (16,000xMIC) and F (160,000xMIC) 2/3 and 1/4 of the implant cavities were S. aureus positive, respectively. By grouping Groups C + D (<10,000xMIC) and Groups E + F (>10,000xMIC) a significant decrease of implant attached bacteria was only seen between the high MIC value group and Group B. Histologically, it was demonstrated that 1,600, 16,000 and 160,000 x MIC resulted in a peri-implant tissue reaction comparable to saline inoculated animals.

Conclusion: In-vivo, the antimicrobial tolerance of the inoculated planktonic bacteria was increased by in-vivo specific factors of acute inflammation. This resulted in bacterial aggregation and biofilm formation which further increased the gentamicin tolerance. Thus, susceptibility patterns in-vitro might not reflect the actual in-vivo susceptibility locally within a developing infectious area.

https://ift.tt/2zfPDk8