Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver

Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).     

Value of Nerve Biopsy in Patients With Latent Malignant Hemopathy and Peripheral Neuropathy: A Case Series

Hematological malignancies include several diseases that may affect the peripheral nervous system (PNS) through various mechanisms. A common and challenging situation is represented by the occurrence of an active peripheral neuropathy in a patient with a supposed inactive hematological disorder.We report clinical, electrophysiological, biological, and pathological data of 8 patients with latent malignant hemopathies (most were considered in remission): B-cell chronic lymphocytic leukemia in 3 patients, B-cell lymphoma in 1 patient, low-grade non-Hodgkin''s lymphoma in 1 patient, Waldenström''s macroglobulinemia in 1 patient, smoldering multiple myeloma in 1 patient, and monoclonal gammopathy of undetermined significance in 1 patient.In all these cases, the nerve biopsy (NB) helped to diagnose the hematological relapse or detect a pathological mechanism linked to the hematological disorder: epineurial lymphocytic infiltration in 5 patients (including one with antimyelin-associated glycoprotein antibodies), cryoglobulin deposits in 1 patient, chronic inflammatory demyelinating polyneuropathy in 1 patient, and necrotizing vasculitis in 1 patient. In each case, pathological findings were crucial to select the adequate treatment, leading to an improvement in the neurological and biological manifestations.These observations illustrate the value of NB and the need for active collaboration between neurologists and hematologists in such cases.     

Small-area distribution of multiple sclerosis incidence in western France: in search of environmental triggers

Background

Despite intensive research over several decades, the etiology of multiple sclerosis (MS) remains poorly understood, although environmental factors are supposedly implicated. Our goal was to identify spatial clusters of MS incident cases at the small-area level to provide clues to local environmental risk factors that might cause or trigger the disease.

Methods

A population-based and multi-stage study was performed in the French Brittany region to accurately ascertain the clinical onset of disease during the 2000–2004 period. The municipality of residence at the time of clinical onset was geocoded. To test for the presence of MS incidence clusters and to identify their approximate locations, we used a spatial scan statistic. We adjusted for socioeconomic deprivation, known to be strongly associated with increased MS incident rates, and scanned simultaneously for areas with either high or low rates. Sensitivity analyses (focusing on relapsing-remitting forms and/or places of residence available within the year following clinical onset) were performed.

Results

A total of 848 incident cases of MS were registered in Brittany, corresponding to a crude annual incidence rate of 5.8 per 100,000 inhabitants. The spatial scan statistic did not find a significant cluster of MS incidence in either the primary analysis (p value ≥ 0.56) or in the sensitivity analyses (p value ≥ 0.16).

Conclusion

The findings of this study indicate that MS incidence is not markedly affected across space, suggesting that in the years preceding the first clinical expression of the disease, no environmental trigger is operative at the small-area population level in the French Brittany region.

     

Circulating cholesterol as a modulator of risk for renal injury in patients with type 2 diabetes

Amelioration of albuminuria may be related to specific constellations of risk factors including race and dyslipidaemia. Circulating cholesterol could mitigate the beneficial effect of antihypertensive therapy. We assessed whether cholesterol affected the remission of urinary albumin in patients with type 2 diabetes of white, Caucasian and non-white origin. We studied 100 patients (African and Asian: n=57 and Caucasian: n=43) with type 2 diabetes and newly diagnosed microalbuminuria who received intensified and structured care for a median (IQ range) of 41 (32-48) months. Microalbuminuria remitted in 20% and progressed in 12% of patients. In those with uncontrolled systolic hypertension (>140 mmHg) systolic blood pressure fell by a mean (95% CI) of -9.4 (-3.8 to -15.11)mmHg; p=0.002. The change in urinary albumin excretion with time varied inversely with baseline systolic blood pressure (r=-0.25; p=0.04). At 3 years follow-up the decrement in blood pressure was significant for those patients in the regression group (-19.6[16.8]mmHg; p=0.005). In patients of African origin, systolic blood pressure was higher than in the other groups and correlated with cholesterol concentrations (r=0.44; p=0.04). Baseline systolic blood pressure and total cholesterol (odds ratio [95%CI]) were independent determinants of remission and progression of microalbuminuria (1.04[1.006-1.064]; p=0.02 and 1.75[1.03-2.95]; p=0.04). Patients with higher total cholesterol and baseline urinary albumin excretion were less likely to go into remission. Blood pressure correlated with cholesterol concentrations in patients of African origin. Specific cholesterol lowering strategies may benefit certain patients groups at high risk of renal disease.     

Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin complex

We report the synthesis and biological characterization of 3-(pyrimidin-4-yl)-7-azaindoles (meriolins), a chemical hybrid between the natural products meridianins and variolins, derived from marine organisms. Meriolins display potent inhibitory activities toward cyclin-dependent kinases (CDKs) and, to a lesser extent, other kinases (GSK-3, DYRK1A). The crystal structures of 1e (meriolin 5) and variolin B (Bettayeb, K.; Tirado, O. M.; Marionneau-Lambert, S.; Ferandin, Y.; Lozach, O.; Morris, J.; Mateo-Lozano, S.; Drückes, P.; Sch?chtele, C.; Kubbutat, M.; Liger, F.; Marquet, B.; Joseph, B.; Echalier, A.; Endicott, J.; Notario, V.; Meijer, L. Cancer Res. 2007, 67, 8325-8334) in complex with CDK2/cyclin A reveal that the two inhibitors are orientated in very different ways inside the ATP-binding pocket of the kinase. A structure-activity relationship provides further insight into the molecular mechanism of action of this family of kinase inhibitors. Meriolins are also potent antiproliferative and proapoptotic agents in cells cultured either as monolayers or in spheroids. Proapoptotic efficacy of meriolins correlates best with their CDK2 and CDK9 inhibitory activity. Meriolins thus constitute a promising class of pharmacological agents to be further evaluated against the numerous human diseases that imply abnormal regulation of CDKs including cancers, neurodegenerative disorders, and polycystic kidney disease.