Repurposing FDA-approved drugs for anti-aging therapies

There is great interest in drugs that are capable of modulating multiple aging pathways, thereby delaying the onset and progression of aging. Effective strategies for drug development include the repurposing of existing drugs already approved by the FDA for human therapy. FDA approved drugs have known mechanisms of action and have been thoroughly screened for safety. Although there has been extensive scientific activity in repurposing drugs for disease therapy, there has been little testing of these drugs for their effects on aging. The pool of FDA approved drugs therefore represents a large reservoir of drug candidates with substantial potential for anti-aging therapy. In this paper we employ FINDSITE^comb, a powerful ligand homology modeling program, to identify binding partners for proteins produced by temperature sensing genes that have been implicated in aging. This list of drugs with potential to modulate aging rates was then tested experimentally for lifespan and healthspan extension using a small invertebrate model. Three protein targets of the rotifer Brachionus manjavacas corresponding to products of the transient receptor potential gene 7, ribosomal protein S6 polypeptide 2 gene, or forkhead box C gene, were screened against a compound library consisting of DrugBank drugs including 1347 FDA approved, non-nutraceutical molecules. Twenty nine drugs ranked in the top 1 % for binding to each target were subsequently included in our experimental analysis. Continuous exposure of rotifers to 1 µM naproxen significantly extended rotifer mean lifespan by 14 %. We used three endpoints to estimate rotifer health: swimming speed (mobility proxy), reproduction (overall vitality), and mitochondria activity (cellular senescence proxy). The natural decline in swimming speed with aging was more gradual when rotifers were exposed to three drugs, so that on day 6, mean swimming speed of females was 1.19 mm/s for naproxen (P = 0.038), 1.20 for fludarabine (P = 0.040), 1.35 for hydralazine (P = 0.038), as compared to 0.88 mm/s in the control. The average reproduction of control females in the second half of their reproductive lifespan was 1.08 per day. In contrast, females treated with 1 µM naproxen produced 1.4 offspring per day (P = 0.027) and females treated with 10 µM fludarabine or 1 µM hydralazine produced 1.72 (P = <0.001) and 1.66 (P = 0.001) offspring per day, respectively. Mitochondrial activity naturally declines with rotifer aging, but B. manjavacas treated with 1 µM hydralazine or 10 µM fludarabine retained 49 % (P = 0.038) and 89 % (P = 0.002) greater mitochondria activity, respectively, than untreated controls. Our results demonstrate that coupling computation to experimentation can quickly identify new drug candidates with anti-aging potential. Screening drugs for anti-aging effects using a rotifer bioassay is a powerful first step in identifying compounds worthy of follow-up in vertebrate models. Even if lifespan extension is not observed, certain drugs could improve healthspan, slowing age-dependent losses in mobility and vitality.     

Clinical profile of medicolegal cases presenting to the eye casualty in a tertiary care center in India

Purpose:The purpose of this study was to analyze the clinical profile of medicolegal cases (MLCs) presenting to the eye casualty in a tertiary care hospital.Results:Out of 188 MLCs, 164 (87.2%) were male. Mean age (±standard deviation) was 31.6 (±12.7) years. Age ranged from 7 to 75 years. Twenty-six (13.8%) patients had bilateral involvement. The fist was the most common mode of injury, which was seen in 109 (58%) cases. A total of 27 (14.3%) patients had associated extraocular injury. No evidence of ocular or orbital trauma (malingering) could be found in 13 (7%) patients. Mechanical trauma was present in 169 (90%) patients with injury to globe in 129 (69%) patients and injury to lid or orbit without damage to the globe in 40 (21%) patients. Chemical injury was observed in 6 (3%) patients. Closed globe injury (CGI) was seen in 116 eyes and open globe injury (OGI) was noted in 29 eyes. The most common type of injury, zone, pupil, and grade of injury in CGI were Type A or contusion (79%), Zone I (72%), Pupil B (absence of relative afferent pupillary defect) in 95%, and Grade A [visual acuity (VA) ≥20/40] in 68% of the eyes, respectively. The most common type of injury, zone, pupil, and grade of injury in OGI were Type B or penetrating (48%), Zone II (38%), Pupil B (59%), and Grade D (VA 4/200-light perception) (42%), respectively.Conclusions:The most common form and mode of ocular injury in MLC were closed globe injury and fist, respectively. The most common type of injury in CGI and OGI was contusion and penetrating injury, respectively.     

Mid-term results of Miller−Galante unicompartmental knee replacement for medial compartment knee osteoarthritis

Background

The purpose of this study is to analyse and report the mid-term results of 175 unicompartmental knee replacement (UKR) procedures performed for medial compartment knee arthritis from January 2001 to January 2010.

Materials and methods

The cohort participants were selected after stringent inclusion criteria and the average follow-up was 5.6 years (range 2–10 years). The fixed-bearing UKR procedure was carried out on all patients.

Results

The pre-operative mean knee range of movement improved from 100° ± 11.3° to 118.3° ± 12° (p value <0.001). The pre-operative mean Knee Society (KS) knee and functional score improved from 47 ± 5.5 and 55.1 ± 4.6 to 91.8 ± 9.2 and 92 ± 10.1 (p value <0.001), respectively. The revision rate of the cohort was 4 % (seven knees) and implant survival rate was 96 % at the end of 10 years; 87 % of the cohort were satisfied with the procedure and had a normal gait pattern. In this study, there was no statistical difference between groups with a body mass index (BMI) ≤30 kg/m² and those with a BMI ≥30 kg/m², and between groups aged ≤55 years and those aged ≥55 years, in clinical and functional outcome following UKR.

Conclusion

This study confirms that fixed-bearing UKR gives excellent results in patients with medial compartment knee arthritis who comply with the inclusion criteria. Age and BMI were not considered to influence the clinical and functional outcomes.Level of evidence-III.

     

NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition

AIMS: The possible contribution of the cardiac mitochondrial permeability transition pore (PTP) towards the cardioprotective effects of Na(+)-H(+) exchanger-1 (NHE-1) inhibition was studied in hearts subjected to ischaemia/reperfusion (IR). METHODS AND RESULTS: Langendorff-perfused rat hearts were subjected to 40 min of global ischaemia and 60 min of reperfusion in the presence or absence of the NHE-1 specific inhibitor AVE-4890 (AVE, 5 microM). Mitochondrial PTP opening was determined in the intact heart using 2-deoxy-[(3)H]-glucose entrapment and in isolated mitochondria by monitoring the decrease of the calcium-induced light scattering. Mitochondrial respiration was measured with a Clark-type oxygen electrode whereas release of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) and levels of cleaved poly-(ADP-ribose) polymerase (PARP) were analysed by western blotting. IR induced mitochondrial PTP opening, which was inhibited by 28% (P < 0.05) with AVE treatment. Mitochondria isolated from AVE-treated hearts demonstrated significantly less calcium-induced swelling and higher substrate oxidation at complex I and II as well as cytochrome c oxidase and citrate synthase activity. AVE treatment also suppressed IR-induced release of AIF and EndoG from mitochondria, prevented the IR-induced rise in cleaved PARP levels, and was associated with significantly enhanced postischaemic recovery of left ventricular developed pressure and a significant decrease in lactate dehydrogenase release. AVE did not affect PTP opening directly in isolated mitochondria. CONCLUSION: The beneficial effect of NHE-1 inhibition in hearts subjected to IR is associated with attenuation of mitochondrial PTP opening and apoptosis and the resultant mitochondrial dysfunction. The effect of AVE on PTP opening most likely is indirect, as pore opening was not affected by direct administration of AVE to mitochondrial suspensions.     

Signalling mechanisms underlying the metabolic and other effects of adipokines on the heart

Adipokines represent a family of proteins released by adipocytes that affect various biological processes including metabolism, satiety, inflammation, and cardiovascular function. The first adipokine to be identified is leptin, a product of the obesity gene whose primary function is to act as a satiety factor. However, it is now recognized that leptin and many of the newly discovered adipokines produce effects on numerous organ systems including the heart. Indeed, various adipokines including leptin, adiponectin, and apelin exert potent and diverse cardiovascular effects which are mediated by their specific receptors and involve complex and multifaceted cell-signalling pathways. Among these are effects on the heart as well as blood pressure where leptin has been proposed to potentially contribute to obesity-related hypertension. In this review, we focus primarily on the diverse effects of adipokines on the heart and discuss the potential cell-signalling mechanisms underlying their actions. The potential role of adipokines in the regulation of cardiac metabolism and function is discussed. Discussion is also presented on the emerging role, both deleterious and salutary, of various adipokines in heart disease with an examination of the possible underlying mechanisms which contribute to these effects.