High-voltage-gated calcium channels have pivot role in the cellular and molecular mechanisms of various neurological disorders, including epilepsy. Similar to other calcium channels, P/Q-type calcium ...channels (Ca
v
2.1) are also responsible for vesicle release at synaptic terminals. Up to date, there are very limited reports showing the mechanisms of Ca
v
2.1 in epileptogenesis. In the present study, we investigated the anticonvulsive and neuroprotective effects of ω-agatoxin IVA, a specific Ca
v
2.1 blocker, in a chemical kindling model of epileptogenesis. Righting reflex and inclined plane tests were used to assess motor coordination. Electroencephalography was recorded for electrophysiological monitoring of seizure activity in freely moving rats. Immunohistochemical analyses were performed for brain-derived neurotrophic factor (BDNF) and cleaved caspase-3 expressions in the prefrontal cortex, striatum, hippocampus, and thalamic nucleus. ω-Agatoxin IVA injected into the right lateral ventricle significantly prolonged the onset of seizures in a dose-dependent manner. In addition, repeated intraperitoneal administrations of ω-agatoxin IVA significantly suppressed the development of kindling and epileptic discharges without altering motor coordination. In addition, ω-agatoxin IVA significantly increased BDNF expressions, and decreased cleaved caspase-3 expressions in the brain when compared to PTZ + saline group. Our current study emphasizes the significance of the inhibition of P/Q type calcium channels by ω-agatoxin IVA, which suppresses the development of epileptogenesis and provides a new potential pathway for epilepsy treatment.
Poleward range expansion of marine organisms is commonly attributed to anthropogenic ocean warming. However, the extent to which a single species can migrate poleward remains unclear. In this study, ...we used molecular data to examine the current distribution of the Pocillopora damicornis species complex in Taiwan waters and applied niche modeling to predict its potential range through the end of the 21st Century. The P. damicornis species complex is widespread across shallow, tropical and subtropical waters of the Indo-Pacific regions. Our results revealed that populations from subtropical nonreefal coral communities are P. damicornis, whose native geographical ranges are approximately between 23°N and 35°N. In contrast, those from tropical reefs are P. acuta. Our analysis of 50 environmental data layers demonstrated that the concentrations of CaCO3 polymorphs had the greatest contributions to the distributions of the two species. Future projections under intermediate shared socioeconomic pathways (SSP) 2–4.5 and very high (SSP5–8.5) scenarios of greenhouse gas emissions showed that while sea surface temperature (SST) isotherms would shift northwards, saturation isolines of two CaCO3 polymorphs, calcite (Ωcal) and aragonite (Ωarag), would shift southwards by 2100. Subsequent predictions of future suitable habitats under those conditions indicated that distinct delimitation of geographical ranges for the two species would persist, and neither would extend beyond its native geographical zones, indicating that tropical Taiwan waters are the northern limit for P. acuta. In contrast, subtropical waters are the southern limit for P. damicornis. We concluded that the decline in CaCO3 saturation would make high latitudes less inhabitable, which could be one of the boundary elements that limit poleward range expansion driven by rising SSTs and preserve the latitudinal diversity gradient (LDG) on Earth. Consequently, poleward migration of tropical reef corals to cope with warming oceans should be reevaluated.
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•Species range expansion is constrained by geological time and evolutionary pace.•Poleward migration of tropical species is challenged by molecular evidence.•Populations of similar morphology in two geographical zones are distinct species.•Range fluctuations would only occur within species' native geographic zone by 2100.•Tropical corals migrate poleward to cope with rising SST should be re-evaluated.
The inducible nitric oxide signaling (iNOS) pathway is associated with poor prognosis in triple-negative breast cancer (TNBC). Prior studies using in vivo models showed that inhibition of the iNOS ...signaling pathway using the pan-NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) reduced tumor growth and enhanced survival in patients with TNBC. Here, we report a first-in-class phase 1/2 trial of L-NMMA combined with taxane for treating patients with chemorefractory, locally advanced breast cancer (LABC) or metastatic TNBC. We also examined immune cell correlates of chemotherapy response. 35 patients with metastatic TNBC were recruited: 15 in the phase 1 trial and 24 in the phase 2 trial (including 4 recommended phase 2 dose patients from the phase 1 trial). The overall response rate was 45.8% (11 of 24): 81.8% (9 of 11) for patients with LABC and 15.4% (2 of 13) for patients with metastatic TNBC. Among the patients with LABC, three patients had a pathological complete response at surgery (27.3%). Grade ≥3 toxicity was noted in 21% of patients; however, no adverse events were attributed to L-NMMA. Immune cells analyzed by CyTOF indicated that chemotherapy nonresponders showed greater expression of markers associated with M2 macrophage polarization and increased concentrations of circulating IL-6 and IL-10 cytokines. In contrast, chemotherapy responders showed an increase in CD15
neutrophils in blood, as well as a decrease in arginase (a marker of protumor N2 neutrophils) in tumor biopsies obtained at the end of treatment. L-NMMA combined with taxane warrants further investigation in larger clinical studies of patients with breast cancer.
This book presents a broad overview of the theory and applications of structure topology and symplectic geometry. Over six chapters, the authors cover topics such as linear operators, Omega and ...Clifford algebra, and quasiconformal reflection across polygonal lines. The book also includes four interesting case studies on time series analysis in practice. Finally, it provides a snapshot of some current trends and future challenges in the research of symplectic geometry theory. Structure Topology and Symplectic Geometry is a resource for scholars, researchers, and teachers in the field of mathematics, as well as researchers and students in engineering.
Bifactor measurement models are increasingly being applied to personality and psychopathology measures (Reise, 2012). In this work, authors generally have emphasized model fit, and their typical ...conclusion is that a bifactor model provides a superior fit relative to alternative subordinate models. Often unexplored, however, are important statistical indices that can substantially improve the psychometric analysis of a measure. We provide a review of the particularly valuable statistical indices one can derive from bifactor models. They include omega reliability coefficients, factor determinacy, construct reliability, explained common variance, and percentage of uncontaminated correlations. We describe how these indices can be calculated and used to inform: (a) the quality of unit-weighted total and subscale score composites, as well as factor score estimates, and (b) the specification and quality of a measurement model in structural equation modeling.
Inflammation in arterial walls leads to coronary artery disease (CAD). We previously reported that a high omega‐3 fatty index was associated with prevention of progression of coronary ...atherosclerosis, a disease of chronic inflammation in the arterial wall. However, the mechanism of such benefit is unclear. The two main omega‐3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors of specialized pro‐resolving lipid mediators (SPMs)–resolvins and maresins–which actively resolve chronic inflammation. To explore whether SPMs are associated with coronary plaque progression, levels of SPMs and proinflammatory mediators (leukotriene B4 LTB4 and prostaglandins) were measured using liquid chromatography‐tandem mass spectrometry in 31 statin‐treated patients with stable CAD randomized to either EPA and DHA, 3.36 g daily, or no EPA/DHA (control). Coronary plaque volume was measured by coronary computed tomographic angiography at baseline and at 30‐month follow‐up. Higher plasma levels of EPA+DHA were associated with significantly increased levels of two SPMs–resolvin E1 and maresin 1–and 18‐hydroxy‐eicosapentaenoic acid (HEPE), the precursor of resolvin E1. Those with low plasma EPA+DHA levels had a low (18‐HEPE+resolvin E1)/LTB4 ratio and significant plaque progression. Those with high plasma EPA+DHA levels had either low (18‐HEPE+resolvin E1)/LTB4 ratios with significant plaque progression or high (18‐HEPE+resolvin E1)/LTB4 ratios with significant plaque regression. These findings suggest that an imbalance between pro‐resolving and proinflammatory lipid mediators is associated with plaque progression and potentially mediates the beneficial effects of EPA and DHA in CAD patients.
•High glucose levels in gestational diabetes mellitus (GDM) dams.•GDM induction marginally lowered docosahexaenoic acid levels in offspring brain.•The offspring of GDM dams showed impaired cognition ...at 3 months of age.•Supplementing omega 3 fatty acids improved docosahexaenoic acid and glucose levels.•Omega 3 fatty acid supplementation improved cognition.
Various mechanisms through which maternal diet influences offspring brain development in gestational diabetes mellitus (GDM) remains unclear. We speculate that prenatal omega 3 fatty acids will improve the levels of brain neurotrophins and vascular endothelial growth factor (VEGF), an angiogenic factor leading to improved cognitive performance in the offspring. GDM was induced in Wistar rats using streptozotocin. They were assigned to either control, GDM or GDM+O (GDM + omega-3 fatty acid supplementation). The offspring were followed till 3 mo of age and cognitive assessment was undertaken. Data analysis was carried out using one-way ANOVA followed by LSD test. GDM induction increased (p < 0.01) dam glucose levels and lowered brain derived neurotrophic factor (BDNF) levels (p = 0.056) in the offspring at birth. At 3 months, GDM group showed significantly lower levels of neurotrophic tyrosine kinase receptor-2 (NTRK-2) and VEGF, lower mRNA levels of NTRK-2 and cAMP response element-binding protein (CREB) (P < 0.05 for all) as compared to control. The GDM offspring had a higher escape latency (p < 0.01), made lesser % correct choices and more errors (p < 0.05 for both). Prenatal supplementation with omega 3 polyunsaturated fatty acids was beneficial since it ameliorated some of the adverse effects of GDM.
Pyruvate dehydrogenase kinases (PDKs) are promising therapeutic targets that have received increasing attentions in cancer metabolism. In this paper, we report the synthesis and biological evaluation ...of a series of novel dichloroacetophenones as potent PDKs inhibitors. Structure-activity relationship analysis enabled us to identify a potent compound 6u, which inhibited PDKs with an EC50 value of 0.09 μM, and reduced various cancer cells proliferation with IC50 values ranging from 1.1 to 3.8 μM, while show weak effect against non-cancerous L02 cell (IC50 > 10 μM). In the A375 xenograft model, 6u displayed an obvious antitumor activity at a dose of 5 mg/kg, but with no negative effect to the mice weight. Molecular docking suggested that 6u formed direct hydrogen bond interactions with Ser75 and Gln61 in PDK1, and meanwhile the aniline skeleton in 6u was sandwiched by the conserved hydrophobic residues Phe78 and Phe65, which contribute to the biochemical activity improvement. Moreover, 6u induced A375 cell apoptosis and cell arrest in G1 phase, and inhibited cancer cell migration. In addition, 6u altered glucose metabolic pathway in A375 cell by decreasing lactate formation and increasing ROS production and OCR consumption, which could serve as a potential modulator to reprogram the glycolysis pathway in cancer cell.
Herein a novel PDK inhibitor 6u was designed and synthesized, which exhibited an EC50 value of 0.09 μM against PDKs, and an IC50 value of 1.1 μM against A375. Display omitted
•Compound 6u inhibited PDKs with an EC50 value of 0.09 µM, outperformed DAP (EC50 > 80 µM) and DAP-64 (EC50 = 0.33 µM).•Compound 6u showed cytotoxicity to A375 (IC50 = 1.1 µM), more potent than DAP (IC50 = 16.9 µM) and DAP-64 (IC50 = 4.9 µM).•Compound 6u is an effective in A375 xenograft model at a dose of 5 mg/kg.
Gastrointestinal toxicity (GIT) is a debilitating side effect of Irinotecan (CPT-11) and limits its clinical utility. Gut dysbiosis has been shown to mediate this side effect of CPT-11 by increasing ...gut bacterial β-glucuronidase (GUSB) activity and impairing the intestinal mucosal barrier (IMB). We have recently shown the opposing effects of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) on the gut microbiome. We hypothesized that elevated levels of tissue n-3 PUFA with a decreased n-6/n-3 PUFA ratio would reduce CPT-11-induced GIT and associated changes in the gut microbiome. Using a unique transgenic mouse (FAT-1) model combined with dietary supplementation experiments, we demonstrate that an elevated tissue n-3 PUFA status with a decreased n-6/n-3 PUFA ratio significantly reduces CPT-11-induced weight loss, bloody diarrhea, gut pathological changes, and mortality. Gut microbiome analysis by 16S rRNA gene sequencing and QIIME2 revealed that improvements in GIT were associated with the reduction in the CPT-11-induced increase in both GUSB-producing bacteria (e.g.,
) and GUSB enzyme activity, decrease in IMB-maintaining bacteria (e.g.,
), IMB dysfunction and systemic endotoxemia. These results uncover a host-microbiome interaction approach to the management of drug-induced gut toxicity. The prevention of CPT-11-induced gut microbiome changes by decreasing the tissue n-6/n-3 PUFA ratio could be a novel strategy to prevent chemotherapy-induced GIT.
Ziconotide (ZIC) is an N-type calcium channel antagonist for treating severe chronic pain that is intolerable, or responds poorly to the administration of other drugs, such as intrathecal morphine ...and systemic analgesics. As it can only work in the brain and cerebrospinal fluid, intrathecal injection is the only administration route for ZIC. In this study, borneol (BOR)-modified liposomes (LIPs) were fused with exosomes from mesenchymal stem cells (MSCs) and loaded with ZIC to prepare microneedles (MNs) to improve the efficiency of ZIC across the blood-brain barrier. To evaluate local analgesic effects of MNs, the sensitivity of behavioral pain to thermal and mechanical stimuli was tested in animal models of peripheral nerve injury, diabetes-induced neuropathy pain, chemotherapy-induced pain, and ultraviolet-B (UV-B) radiation-induced neurogenic inflammatory pain. BOR-modified LIPs loaded with ZIC were spherical or nearly spherical, with a particle size of about 95 nm and a Zeta potential of −7.8 mV. After fusion with MSC exosomes, the particle sizes of LIPs increased to 175 nm, and their Zeta potential increased to −3.8 mV. The nano-MNs constructed based on BOR-modified LIPs had good mechanical properties and could effectively penetrate the skin to release drugs. The results of analgesic experiments showed that ZIC had a significant analgesic effect in different pain models. In conclusion, the BOR-modified LIP membrane-fused exosome MNs constructed in this study for delivering ZIC provide a safe and effective administration for chronic pain treatment, as well as great potential for clinical application of ZIC.
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•To provide a transdermal delivery system for the delivery of ziconotide.•ZIC@MSCEXO/LIP-BOR can improve the ability of crossing the BBB effectively.•ZIC@MSCEXO/LIP-BOR have the characteristics of liposomes and exosomes.•Various pain models were established to evaluate the analgesic effect.•MN#ZIC@MSCEXO/LIP-BOR has high biocompatibility and analgesic effect.
