A Chemical Analog of Curcumin as an Improved Inhibitor of Amyloid Abeta Oligomerization

Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin

Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition

Given the high frequency of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL), inhibition of the γ-secretase complex remains an attractive target to prevent ligand-independent release of the cytoplasmic tail and oncogenic NOTCH1 signaling. However, four different γ-secretase complexes exist, and available inhibitors block all complexes equally. As a result, these cause severe “on-target” gastrointestinal tract, skin, and thymus toxicity, limiting their therapeutic application. Here, we demonstrate that genetic deletion or pharmacologic inhibition of the presenilin-1 (PSEN1) subclass of γ-secretase complexes is highly effective in decreasing leukemia while avoiding dose-limiting toxicities. Clinically, T-ALL samples were found to selectively express only PSEN1-containing γ-secretase complexes. The conditional knockout of Psen1 in developing T cells attenuated the development of a mutant NOTCH1-driven leukemia in mice in vivo but did not abrogate normal T cell development. Treatment of T-ALL cell lines with the selective PSEN1 inhibitor MRK-560 effectively decreased mutant NOTCH1 processing and led to cell cycle arrest. These observations were extended to T-ALL patient-derived xenografts in vivo, demonstrating that MRK-560 treatment decreases leukemia burden and increased overall survival without any associated gut toxicity. Therefore, PSEN1-selective compounds provide a potential therapeutic strategy for safe and effective targeting of T-ALL and possibly also for other diseases in which NOTCH signaling plays a role

Structure–activity study of N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a bitopic ligand that acts as a negative allosteric modulator of the dopamine D2 receptor

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharma- cology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R

Why Pleiotropic Interventions are Needed for Alzheimer's Disease

Alzheimer's disease (AD) involves a complex pathological cascade thought to be initially triggered by the accumulation of β-amyloid (Aβ) peptide aggregates or aberrant amyloid precursor protein (APP) processing. Much is known of the factors initiating the disease process decades prior to the onset of cognitive deficits, but an unclear understanding of events immediately preceding and precipitating cognitive decline is a major factor limiting the rapid development of adequate prevention and treatment strategies. Multiple pathways are known to contribute to cognitive deficits by disruption of neuronal signal transduction pathways involved in memory. These pathways are altered by aberrant signaling, inflammation, oxidative damage, tau pathology, neuron loss, and synapse loss. We need to develop stage-specific interventions that not only block causal events in pathogenesis (aberrant tau phosphorylation, Aβ production and accumulation, and oxidative damage), but also address damage from these pathways that will not be reversed by targeting prodromal pathways. This approach would not only focus on blocking early events in pathogenesis, but also adequately correct for loss of synapses, substrates for neuroprotective pathways (e.g., docosahexaenoic acid), defects in energy metabolism, and adverse consequences of inappropriate compensatory responses (aberrant sprouting). Monotherapy targeting early single steps in this complicated cascade may explain disappointments in trials with agents inhibiting production, clearance, or aggregation of the initiating Aβ peptide or its aggregates. Both plaque and tangle pathogenesis have already reached AD levels in the more vulnerable brain regions during the “prodromal” period prior to conversion to “mild cognitive impairment (MCI).” Furthermore, many of the pathological events are no longer proceeding in series, but are going on in parallel. By the MCI stage, we stand a greater chance of success by considering pleiotropic drugs or cocktails that can independently limit the parallel steps of the AD cascade at all stages, but that do not completely inhibit the constitutive normal functions of these pathways. Based on this hypothesis, efforts in our laboratories have focused on the pleiotropic activities of omega-3 fatty acids and the anti-inflammatory, antioxidant, and anti-amyloid activity of curcumin in multiple models that cover many steps of the AD pathogenic cascade (Cole and Frautschy, Alzheimers Dement 2:284–286, 2006)

Images in Radiology - Complete Hydatidiform Mole With Live Pregnancy In A Twin Gestation

A 29-year-old primigravida, 22 weeks of gestation, complained of abdominal lump, pain in the abdomen, episodes of vasovagal attacks, headache and intermittent episodes of spotting. On physical examination she was normotensive and fundal height was 20 cm. Two big firm masses were palpable in the lumbar regions bilaterally. The foetal heartbeats were ausculated normally. Antenatal ultrasound examination revealed a live foetus, which had measurements consistent with 22 weeks of gestation. The placenta was anterior in location and showed grade I maturity, without any focal lesion. Another markedly enlarged mass, separate from the anterior normal placenta, with small cystic areas and increased echogenicity was seen along the posterior uterine wall, typically showing "snow storm" appearance. These changes were consistent with hydatidiform molar changes most probably in the second placenta (Figure 1). Two large extrauterine, predominantly cystic masses were also seen in the lumbar regions bilaterally near the fundus of the uterus. They were showing multiple cystic areas within it and measured approximately 15 X 15 cm in size. These were suggestive of theca lutein cysts in both enlarged ovaries in association with the hydatidiform mole (Figure 2). Serum titre of beta-HCG at 22 weeks was 1,20,000 mIU/ml. Chest x-ray, thyroid and liver function tests were normal. Repeat ultrasound at 24 weeks revealed exacerbation of placentomegaly and onset of polyhydramnios. The symptoms continued to increase and the patient underwent spontaneous delivery at 28 weeks of gestation and delivered a baby with weight of 1450 grams. The normal placenta was delivered within 15 minutes after birth and the abnormal posterior placenta was removed subsequently using surgical approach. The histopathology of the abnormal posterior placenta revealed hydatidiform (grapelike, cystic) degeneration of chorionic villi with inadequate vascularisation and abnormal, excessive proliferation of placental trophoblasts. Karyotype of the baby's white cells and mole revealed normal 46-XX chromosomal patterns. Mother's chest radiograph, abdomino-pelvic sonography and serum CA-125 marker study done post partum did not reveal any abnormality. She was not give any chemotherapy

Percutaneous conservative management of emphysematous pyelonephritis

Sir, A 75-year-old lady presented with pain in left flank and fever. There was tenderness in left renal angle. On laboratory investigation, patient was found to be a diabetic and in renal failure. A plain film of abdomen showed unusual presence of air in the left renal fossa. Ultrasonography (USG) revealed non-visualisation of left kidney in left renal fossa with strong reflective echoes ('gassed out kidney'), which was consistent with emphysematous pyelonephritis. Plain computed tomographic (CT) scan revealed the presence of air collections in the left renal and perirenal space with fluid collections. The opposite kidney was unremarkable. Blood culture growed E. coli. Because of high risk for anaesthesia the decision of immediate nephrectomy was deferred. It was decided to manage the patient conservatively with immediate nephrostomy. A percutaneous nephrostomy was performed with Mallecot catheter under ultrasound guidance and the patient was kept on antibiotics and insulin. The patient showed immediate improvement in clinical status within 24 hours. Follow up CT scan demonstrated resolution of perinephric collection