Different effects of the nonsteroidal anti-inflammatory drugs meclofenamate sodium and naproxen sodium on proteasome activity in cardiac cells.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) like meclofenamate sodium (MS), used to reduce pain, has been associated with an increased risk of cardiovascular disease (CVD). Naproxen (NAP), another NSAID, is not associated with increased risk of CVD. The molecular mechanism(s) by which NSAIDs induce CVD is unknown. We investigated the effects of MS and NAP on protein homeostasis and cardiotoxicity in rat cardiac H9c2 cells and murine neonatal cardiomyocytes. MS, but not NAP, significantly inhibited proteasome activity and reduced cardiac cell viability at pharmacological levels found in humans. Although proteasome subunit gene and protein expression were unaffected by NSAIDs, MS treated cell lysates showed higher 20S proteasome content, while purified proteasomes from MS treated cells had lower proteasome activity and higher levels of oxidized subunits than proteasomes from control cells. Addition of exogenous proteasome to MS treated cells improved cell viability. Both MS and NAP increased ROS production, but the rate of ROS production was greater in MS than in NAP treated cells. The ROS production is likely from mitochondria, as MS inhibited mitochondrial Complexes I and III, major sources of ROS, while NAP inhibited Complex I. MS also impaired mitochondrial membrane potential while NAP did not. Antioxidants were able to prevent the reduced cell viability caused by MS treatment. These results suggest that NSAIDs induce cardiotoxicity by a ROS dependent mechanism involving mitochondrial and proteasome dysfunction and may explain why some NSAIDs should not be given to patients for long periods.

Phlpp inhibitors block pain and cartilage degradation associated with osteoarthritis.

Phlpp protein phosphatases are abnormally abundant within human osteoarthritic articular chondrocytes and may contribute to the development of osteoarthritis. Mice lacking Phlpp1 were previously shown to be resistant to post-traumatic osteoarthritis. Here a small molecule with therapeutic properties that inhibits Phlpp1 and Phlpp2 was tested for its ability to slow post-traumatic OA in mice and to stimulate anabolic pathways in human articular cartilage from OA joints. PTOA was induced in male C57Bl/6 mice by surgically destabilizing the meniscus. Seven weeks after surgery, mice received a single intra-articular injection of the Phlpp inhibitor NSC117079 or saline. Mechanical allodynia was measured with von Frey assays, mobility was tracked in an open field system, and cartilage damage was assessed histologically. A single intra-articular injection of the Phlpp inhibitor NSC117079 attenuated mechanical allodynia and slowed articular cartilage degradation in joints with a destabilized meniscus. Animals treated with the Phlpp inhibitor 7 weeks after injury maintained normal activity levels, while those in the control group traveled shorter distances and were less active 3 months after the joint injury. NSC117079 also increased production of cartilage extracellular matrix components (glycosaminoglycans and aggrecan) in over 90% of human articular cartilage explants from OA patients and increased phosphorylation of Phlpp1 substrates (AKT2, ERK1/2, and PKC) in human articular chondrocytes. Our results indicate that Phlpp inhibitor NSC117079 is a novel osteoarthritis disease modifying drug candidate that may have palliative affects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1487-1497, 2018.

Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice.

Osteoarthritis (OA) is the leading form of arthritis in the elderly, causing pain, disability, and immobility. OA has been associated with accumulation of senescent cells in or near joints. However, evidence for a causal link between OA and cellular senescence is lacking. Here, we present a novel senescent cell transplantation model involving injection of small numbers of senescent or nonsenescent cells from the ear cartilage of luciferase-expressing mice into the knee joint area of wild-type mice. By using bioluminescence and 18FDG PET imaging, we could track the injected cells in vivo for more than 10 days. Transplanting senescent cells into the knee region caused leg pain, impaired mobility, and radiographic and histological changes suggestive of OA. Transplanting nonsenescent cells had less of these effects. Thus, senescent cells can induce an OA-like state and targeting senescent cells could be a promising strategy for treating OA.

Comparison of subcutaneous versus submuscular expander placement in the first stage of immediate breast reconstruction.

BACKGROUND AND AIM: Tissue expander-based two-stage reconstruction remains the most commonly used technique in immediate breast reconstruction. This study compares the subcutaneous expander placement to the traditional submuscular placement and describes our early experience with the expander insertion plane-choosing algorithm. METHODS: A retrospective study of patients who underwent two-stage immediate breast reconstruction from May 2012 to October 2014 was conducted. All expander insertion planes were chosen using the same algorithm. Expansion, pain, and complications were compared between two groups. RESULTS: The study included 88 patients (158 expanders; 50 subcutaneous and 108 submuscular). The subcutaneous group had a higher intraoperative expansion ratio (p < 0.001), high first postoperative expansion ratio (p < 0.001), shorter duration of expansion (p = 0.02), less number of expansion visits (p = 0.002), and less average pain during admission (p = 0.004). Significant differences in the intraoperative and first postoperative expansion ratios in patients with postmastectomy radiation therapy were also found between the two groups (p = 0.005 and 0.01, respectively). Complications during expansion and after second-stage autologous flap reconstruction were comparable between two groups. CONCLUSION: The subcutaneous expander placement was associated with greater intraoperative and first postoperative expansion, shorter expansion duration, less expansion visits, and less pain. With the expander insertion plane-choosing algorithm, subcutaneous expander placement could be performed with comparable complications rates with the submuscular placement during expansion and after second-stage autologous flap reconstruction. Further studies can be performed due to the lack of long-term complications following second-stage implant reconstruction in the subcutaneous approach.

Successful Surgical Treatment of Severe Calciphylaxis Using a Bilayer Dermal Replacement Matrix.

Cutaneous calciphylaxis is a rare and often intractable disease that involves subcutaneous vascular calcification, ischemia, and subsequent necrosis. Calciphylaxis has an associated 60%-80% mortality rate with sepsis as the leading cause of death. However, despite variable success rates, the proper treatment of calciphylaxis remains controversial. In this case report, the authors present a 42-year-old female who presented with bilateral lower extremity calciphylaxis in conjunction with long-standing liver disease and acute renal failure. Cure of the patient's calciphylaxis was achieved through a surgical approach using staged debridement, placement of a dermal regenerative template (Integra Dermal Regeneration Template, Integra Lifesciences, Plainsboro, NJ), and followed by successful skin grafting. This is the first successful treatment of calciphylaxis in the literature to date using dermal regenerative template material.