The effects of acetylcholinesterase inhibitors on the heart in acute myocardial infarction and heart failure: From cells to patient reports

Cardiovascular diseases remain a major cause of morbidity and mortality worldwide. Cardiovascular diseases such as acute myocardial infarction, ischaemia/reperfusion injury and heart failure are associated with cardiac autonomic imbalance characterized by sympathetic overactivity and parasympathetic withdrawal from the heart. Increased parasympathetic activity by electrical vagal nerve stimulation has been shown to provide beneficial effects in the case of cardiovascular diseases in both animals and patients by improving autonomic function, cardiac remodelling and mitochondrial function. However, clinical limitations for electrical vagal nerve stimulation exist because of its invasive nature, costly equipment and limited clinical validation. Therefore, novel therapeutic approaches which moderate parasympathetic activities could be beneficial for in the case of cardiovascular disease. Acetylcholinesterase inhibitors inhibit acetylcholinesterase and hence increase cholinergic transmission. Recent studies have reported that acetylcholinesterase inhibitors improve autonomic function and cardiac function in cardiovascular disease models. Despite its potential clinical benefits for cardiovascular disease patients, the role of acetylcholinesterase inhibitors in acute myocardial infarction and heart failure remediation remains unclear. This article comprehensively reviews the effects of acetylcholinesterase inhibitors on the heart in acute myocardial infarction and heart failure scenarios from in vitro and in vivo studies to clinical reports. The mechanisms involved are also discussed in this review.     

Testosterone replacement attenuates cognitive decline in testosterone-deprived lean rats,but not in obese rats,by mitigating brain oxidative stress

Testosterone replacement improves metabolic parameters and cognitive function in hypogonadism. However, the effects of testosterone therapy on cognition in obese condition with testosterone deprivation have not been investigated. We hypothesized that testosterone replacement improves cognitive function in testosterone-deprived obese rats by restoring brain insulin sensitivity, brain mitochondrial function, and hippocampal synaptic plasticity. Thirty male Wistar rats had either a bilateral orchiectomy (ORX: O, n = 24) or a sham operation (S, n = 6). ORX rats were further divided into two groups fed with either a normal diet (NDO) or a high-fat diet (HFO) for 12 weeks. Then, ORX rats in each dietary group were divided into two subgroups (n = 6/subgroup) and were given either castor oil or testosterone (2 mg/kg/day, s.c.) for 4 weeks. At the end of this protocol, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity, and brain mitochondrial function were determined. We found that testosterone replacement increased peripheral insulin sensitivity, decreased circulation and brain oxidative stress levels, and attenuated brain mitochondrial ROS production in HFO rats. However, testosterone failed to restore hippocampal synaptic plasticity and cognitive function in HFO rats. In contrast, in NDO rats, testosterone decreased circulation and brain oxidative stress levels, attenuated brain mitochondrial ROS production, and restored hippocampal synaptic plasticity as well as cognitive function. These findings suggest that testosterone replacement improved peripheral insulin sensitivity and decreased oxidative stress levels, but failed to restore hippocampal synaptic plasticity and cognitive function in testosterone-deprived obese rats. However, it provided beneficial effects in reversing cognitive impairment in testosterone-deprived non-obese rats.     

Efficacy of Thai herbal essential oils as green repellent against mosquito vectors

Repellency activity of Thai essential oils derived from ylang ylang (Cananga odorata (Lamk.) Hook.f. & Thomson: Annonaceae) and lemongrass (Cymbopogon citratus (DC.) Stapf: Poaceae) were tested against two mosquito vectors, Aedes aegypti (L.) and Culex quinquefasciatus (Say). There were compared with two chemical repellents (DEET 20% w/w; Sketolene Shield^® and IR3535, ethyl butylacetylaminopropionate 12.5% w/w; Johnson's Baby Clear Lotion Anti-Mosquito^®). Each herbal repellent was applied in three diluents; coconut oil, soybean oil and olive oil at 0.33 μl/cm² on the forearm of volunteers. All herbal repellent exhibited higher repellent activity than IR3535 12.5% w/w, but lower repellent activity than DEET 20% w/w. The C. odorata oil in coconut oil exhibited excellent activity with 98.9% protection from bites of A. aegypti for 88.7 ± 10.4 min. In addition, C. citratus in olive oil showed excellent activity with 98.8% protection from bites of C. quinquefasciatus for 170.0 ± 9.0 min. While, DEET 20% w/w gave protection for 155.0 ± 7.1–182.0 ± 12.2 min and 98.5% protection from bites of two mosquito species. However, all herbal repellent provided lower repellency activity (97.4–98.9% protection for 10.5–88.7 min) against A. aegypti than C. quinquefasciatus (98.3–99.2% protection for 60–170 min). Our data exhibited that C. odorata oil and C. citratus oil are suitable to be used as green repellents for mosquito control, which are safe for humans, domestic animals and environmental friendly.     

Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis

Tumor necrosis factor (TNF) is an important inflammatory cytokine and induces many cellular responses, including inflammation, cell proliferation, apoptosis, and necrosis. It is known that receptor interacting protein (RIP) kinases, RIP1 and RIP3, are key effectors of TNF-induced necrosis, but little is known about how these two RIP kinases mediate this process, although reactive oxygen species (ROS) generation and JNK activation have been suggested to be two downstream events of RIP kinases. Here we report the identification of mixed lineage kinase domain-like, MLKL, as a key RIP3 downstream component of TNF-induced necrosis. Through screening a kinase/phosphatase shRNA library in human colon adenocarcinoma HT-29 cells, we found that knockdown of MLKL blocked TNF-induced necrosis. Our data suggest that MLKL functions downstream of RIP1 and RIP3 and is recruited to the necrosome through its interaction with RIP3. Finally, we found that MLKL is required for the generation of ROS and the late-phase activation of JNK during TNF-induced necrosis. However, because these two events are not involved in TNF-induced necrosis in HT-29 cells, the target of MLKL during TNF-induced necrosis remains elusive. Taken together, our study suggests that MLKL is a key RIP3 downstream component of TNF-induced necrotic cell death.     

Chitin biomass-nifedipine amorphous solid dispersion for enhancement of hydrophobic drug dissolution in aqueous media

Solid dispersions of poorly-water soluble nifedipine using microparticles fabricated from chitin biomass were prepared to improve the drug dissolution in an aqueous medium. After the drug loading and solvent evaporation, the drug loading capacity of 1, 6, and 19 %w/w was obtained. In the microstructure, the drug was dispersed on the porous chitin carrier with minor agglomeration leading to reduced crystallization and improved dissolution, nearly 100%, as compared to the pure nifedipine powder and the physical mixture with chitin. There was an interaction between functional groups of the drug and polymer, consequently the release prolonged for the entire 6 h with the maximum drug solubility of about 300 μg/ml. An in vitro release study showed that nifedipine effectively released from chitin into a simulated gastric releasing medium (pH 1.2). In this case, the release mechanism was best fitted with a Zero-order model based on the Fick's Law in the first 2 h. This research indicated that employing microparticle obtained from chitin biomass in the solid dispersion system lowered the drug recrystallization, facilitated drug release, and provided the sustainability in pharmaceutical science.     

Fractionated stereotactic radiotherapy to the post-operative cavity for radioresistant and radiosensitive brain metastases

Following surgical resection for brain metastases, fractionated stereotactic radiotherapy (FSRT) has been used as an alternative to single dose treatment for large cavities and to reduce risks of late toxicity. The purpose of this study was to evaluate the outcomes of patients treated with FSRT to the post-operative bed for both radioresistant and radiosensitive brain metastases. Between December 2009 and May 2013 a total of 65 patients with newly diagnosed brain metastases were treated with resection followed by FSRT. Patients were treated to a total dose of 20–30 Gy in five fractions. Median planning target volume (PTV) was 16.88 cm³ (range 4.87–128.43 cm³). The median follow-up for all patients was 8.5 months (range 1.1–28.6 months) with a median of 12.9 months for living patients. One and two year Kaplan–Meier estimates of local control were 87.0 and 70.0 %, respectively. Local control at 1 year was 85.6 and 88.0 % for radioresistant and radiosensitive tumors, respectively (p = 0.44). A PTV ≥17 cm³, was associated with local failure, HR 8.63 ((1.44–164.78); p = 0.02). One and two year distant control rates were 50.9 and 46.2 %, respectively with six patients (9.2 %) experiencing leptomeningeal disease. OS rates at 1 and 2 years were 65.2 and 47.5 %, respectively. Survival was significantly associated with recursive partitioning analysis class (p = 0.001) and graded prognostic assessment score (p = 0.005). One case of radionecrosis was noted on follow-up imaging. FSRT in five fractions offers excellent local control in both radiosensitive and radioresistant tumors with minimal toxicity.     

Bacillus thuringiensis Cry4Ba Insecticidal ToxinExploits Leu615 in Its C-Terminal Domain to Interact with a Target Receptor—Aedes aegypti Membrane-Bound Alkaline Phosphatase

In addition to the receptor-binding domain (DII), the C-terminal domain (DIII) of three-domain Cry insecticidal δ-endotoxins from Bacillus thuringiensis has been implicated in target insect specificity, yet its precise mechanistic role remains unclear. Here, the 21 kDa high-purity isolated DIII fragment derived from the Cry4Ba mosquito-specific toxin was achieved via optimized preparative FPLC, allowing direct rendering analyses for binding characteristics toward its target receptor—Aedes aegypti membrane-bound alkaline phosphatase (Aa-mALP). Binding analysis via dotblotting revealed that the Cry4Ba-DIII truncate was capable of specific binding to nitrocellulose-bound Aa-mALP, with a binding signal comparable to its 65 kDa Cry4Ba-R203Q full-length toxin. Further determination of binding affinity via sandwich ELISA revealed that Cry4Ba-DIII exhibited a rather weak binding to Aa-mALP with a dissociation constant (K_d) of ≈1.1 × 10⁻⁷ M as compared with the full-length toxin. Intermolecular docking between the Cry4Ba-R203Q active toxin and Aa-mALP suggested that four Cry4Ba-DIII residues, i.e., Glu⁵²², Asn⁵⁵², Asn⁵⁷⁶, and Leu⁶¹⁵, are potentially involved in such toxin–receptor interactions. Ala substitutions of each residue (E522A, N552A, N576A and L615A) revealed that only the L615A mutant displayed a drastic decrease in biotoxicity against A. aegypti larvae. Additional binding analysis revealed that the L615A-impaired toxin also exhibited a reduction in binding capability to the surface-immobilized Aa-mALP receptor, while two bio-inactive DII-mutant toxins, Y332A and F364A, which almost entirely lost their biotoxicity, apparently retained a higher degree of binding activity. Altogether, our data disclose a functional importance of the C-terminal domain of Cry4Ba for serving as a potential receptor-binding moiety in which DIII-Leu⁶¹⁵ could conceivably be exploited for the binding to Aa-mALP, highlighting its contribution to toxin interactions with such a target receptor in mediating larval toxicity.