Microcystin-LR accelerates follicular atresia in mice via JNK-mediated adherent junction damage of ovarian granulosa cells.

Microcystin-LR (MC-LR), one of aquatic environmental contaminants with reproductive toxicity produced by cyanobacterial blooms, but its toxic effects and mechanisms on the ovary are not fully understood. Here, proteomic techniques and molecular biology experiments were performed to study the potential mechanism of MC-LR-caused ovarian toxicity. Results showed that protein expression profile of ovarian granulosa cells (KK-1) was changed by 17 µg/mL MC-LR exposure. Comparing with the control group, 118 upregulated proteins as well as 97 downregulated proteins were identified in MC-LR group. Function of differentially expressed proteins was found to be enriched in pathways related to adherent junction, such as cadherin binding, cell-cell junction, cell adhesion and focal adherens. Furthermore, in vitro experiments, MC-LR significantly downregulated the expression levels of proteins associated with adherent junction (ß-catenin, N-cadherin, and α-catenin) as well as caused cytoskeletal disruption in KK-1 cells (P < 0.05), indicating that the adherent junction was damaged. Results of in vivo experiments have shown that after 14 days of acute MC-LR exposure (40 µg/kg), damaged adherent junction and an increased number of atretic follicles were observed in mouse ovaries. Moreover, MC-LR activated JNK, an upstream regulator of adherent junction proteins, in KK-1 cells and mouse ovarian tissues. In contrast, JNK inhibition alleviated MC-LR-induced adherent junction damage in vivo and in vitro, as well as the number of atretic follicles. Taken together, findings from the present study indicated that JNK is involved in MC-LR-induced granulosa cell adherent junction damage, which accelerated follicular atresia. Our study clarified a novel mechanism of MC-LR-caused ovarian toxicity, providing a theoretical foundation for protecting female reproductive health from environmental pollutants.

Appropriate use of essential medicines in the elderly: a comparison of the WHO essential medicines list and PIM criteria.

PURPOSE: The elderly are not only threatened by bad medicines (overtreatment) but also by undertreatment with "good" medicines. Symmetry is required in any patient-centred approach to properly treat older people. The purpose of this study was to perfect the development of an EML and criteria according to the advantages of each and promote the appropriate use of essential medicines in the elderly. METHOD: We compared the EML with four PIM criteria and calculated the proportion of essential medicines included in the criteria. We also summarized the rationale for including medicines in each criterion and analysed higher risk drugs and drug risks. RESULTS: Of essential medicines, 26% are included in at least one criterion as PIM. In 11 drug categories of the EML, more than 50% of drugs of each category are included in at least one criterion, and in four categories, all drugs are included. The potentially inappropriate essential medicines (PIEMs) for the elderly focus on cardiovascular drugs and central nervous system drugs. Fifty-nine drugs have been explicitly identified as increasing the risk of falls, increasing mortality and/or having inappropriate long-term use, and the main risk of PIEMs is falls (30.3% of PIEMs). Additionally, 17.9% of essential medicines are labelled as positive drugs in START and/or FORTA (A/B). CONCLUSION: Improving medication information for the elderly in the EML and establishing an essential medicines list for the elderly will promote appropriate drug use in older people worldwide.

Design and evaluation of a brinzolamide drug-resin in situ thermosensitive gelling system for sustained ophthalmic drug delivery.

In this study a brinzolamide drug-resin ophthalmic thermosensitive in situ gelling system was developed and evaluated. Brinzolamide was combined with ion exchange resins to prolong the retention time of drugs in the eye and to reduce ocular and systemic side effects. Poloxamer F127 was used as gelling vehicle in combination with carbopol 934P, which acted as a viscosity-enhancing agent. They were prepared using the cold method. The optimized formulation exhibited a sol-gel transition at 33.2±1.1°C with pseudoplastic flow behavior. This formulation was stable and nonirritant to rabbit eyes. In vitro release studies demonstrated diffusion-controlled release of brinzolamide from the combined solutions over a period of 8 h. In vivo evaluation (the elimination of brinzolamide through tears and absorption of brinzolamide in aqueous humor) indicated that the solution combination was better able to retain the drug than commercial preparations. Thus this formulation is safe for ophthalmic use and significantly increases brinzolamide bioavailability in aqueous humor.