Melatonin inhibits matrix metalloproteinase‐9 activity by binding to its active site

The zinc‐dependent matrix metalloproteinases (MMPs) are key enzymes associated with extracellular matrix (ECM) remodeling; they play critical roles under both physiological and pathological conditions. MMP‐9 activity is linked to many pathological processes, including rheumatoid arthritis, atherosclerosis, gastric ulcer, tumor growth, and cancer metastasis. Specific inhibition of MMP‐9 activity may be a promising target for therapy for diseases characterized by dysregulated ECM turnover. Potent MMP‐9 inhibitors including an indole scaffold were recently reported in an X‐ray crystallographic study. Herein, we addressed whether melatonin, a secretory product of pineal gland, has an inhibitory effect on MMP‐9 function. Gelatin zymographic analysis showed a significant reduction in pro‐ and active MMP‐9 activity in vitro in a dose‐ and time‐dependent manner. In addition, a human gastric adenocarcinoma cell line (AGS) exhibited a reduced (~50%) MMP‐9 expression when incubated with melatonin, supporting an inhibitory effect of melatonin on MMP‐9. Atomic‐level interaction between melatonin and MMP‐9 was probed with computational chemistry tools. Melatonin docked into the active site cleft of MMP‐9 and interacted with key catalytic site residues including the three histidines that form the coordination complex with the catalytic zinc as well as proline 421 and alanine 191. We hypothesize that under physiological conditions, tight binding of melatonin in the active site might be involved in reducing the catalytic activity of MMP‐9. This finding could provide a novel approach to physical docking of biomolecules to the catalytic site of MMPs, which inhibits this protease, to arrest MMP‐9‐mediated inflammatory signals.     

Abwägung oder doch harte Kriterien in der Begutachtung von Läsionen der Rotatorenmanschette

The majority of rotator cuff tears are related to a natural aging process and caused by multifactorial influencing factors. A pure or essentially extrinsic origin due to a traumatic event is rare and is particularly difficult to differentiate because of the frequency of age-related degenerative alterations to the tendons. As the basic understanding of the development of traumatic cuff tears is based mainly on biomechanical studies and empirical observations, assessing the potential link between structural tendon damage and a traumatic event involves a weighing up process of all available medical evidence. This includes the initial clinical examination, assessment of pain and clinical function over time, radiographic imaging, analysis of the injury mechanism and patient history of pre-existing shoulder dysfunction or inherent risk factors as well as operative findings and histological results.     

Low dose of methyltestosterone in ovariectomised rats improves baroreflex sensitivity without geno‐ and cytotoxicity

This study evaluated the effects of the isolated use of a low dose of methyltestosterone (MT) on cardiovascular reflexes and hormonal levels and its geno‐ and cytotoxic safety in ovariectomized rats. Female Wistar rats were divided into four groups (n = 6), respectively: SHAM (received vehicle methylcellulose 0.5%), SHAM + MT (received MT 0.05 mg/kg), OVX (received vehicle), and OVX + MT (received MT). Twenty‐one days after ovariectomy, treatment was given orally daily for 28 days. The Bezold–Jarisch reflex (BJR) was analyzed by measuring the bradycardic and hypotensive responses elicited by phenylbiguanide (PBG) administration. The baroreflex sensitivity (BRS) was evaluated by phenylephrine and sodium nitroprussite. Myocyte hypertrophy was determined by morphometric analysis of H&E stained slides. Biochemical data were analyzed, as well as micronucleus assay. MT improved BRS and increased testosterone values, but did not change estradiol in the OVX group. MT did not promote changes in mean arterial pressure, heart rate, BJR, serum concentrations of troponin I, weight and histopathology of the heart. MT was able to restore the BRS in OVX rats. The geno‐ and cytotoxic safety of the MT was demonstrated by the absence of an increase in the micronucleus (PCEMN) or change in the ratio between normochromatic erythrocytes and polychromatic erythrocytes (NCE/PCE).     

Simultaneous large bi-atrial device-related thrombi

Journal of Thrombosis and Thrombolysis - Simultaneous appearance of a pacemaker-lead associated thrombus and a left atrial appendage closure device related thrombus in a patient with urothelial...