Interaction between theta-phase and spike-timing dependent plasticity simulates theta induced memory effects

Rodent studies suggest that spike timing relative to hippocampal theta activity determines whether potentiation or depression of synapses arise. Such changes also depend on spike timing between pre- and post-synaptic neurons, known as spike-timing-dependent plasticity (STDP). STDP, together with theta-phase-dependent learning, has inspired several computational models of learning and memory. However, evidence to elucidate how these mechanisms directly link to human episodic memory is lacking. In a computational model, we modulate long-term potentiation (LTP) and long-term depression (LTD) of STDP, by opposing phases of a simulated theta rhythm. We fit parameters to a hippocampal cell culture study in which LTP and LTD were observed to occur in opposing phases of a theta rhythm. Further, we modulated two inputs by cosine waves with synchronous and asynchronous phase offsets and replicate key findings in human episodic memory. Learning advantage was found for the synchronous condition, as compared to the asynchronous conditions, and was specific to theta modulated inputs. Importantly, simulations with and without each mechanism suggest that both STDP and theta-phase-dependent plasticity are necessary to replicate the findings. Together, the results indicate a role for circuit-level mechanisms, which bridges the gap between slice preparation studies and human memory.

In Vivo Biocompatible Self-Assembled Nanogel Based on Hyaluronic Acid for Aqueous Solubility and Stability Enhancement of Asiatic Acid

Asiatic acid (AA), a natural triterpene found in Centalla asiatica, possesses polypharmacological properties that can contribute to the treatment and prophylaxis of various diseases. However, its hydrophobic nature and rapid metabolic rate lead to poor bioavailability. The aim of this research was to develop a thermoresponsive nanogel from hyaluronic acid (HA) for solubility and stability enhancement of AA. Poly(N-isopropylacrylamide) (pNIPAM) was conjugated onto HA using a carbodiimide reaction followed by 1H NMR characterization. pNIPAM-grafted HA (HA-pNIPAM) nanogels were prepared with three concentrations of polymer, 0.1, 0.15 and 0.25% w/v, in water by the sonication method. AA was loaded into the nanogel by the incubation method. Size, morphology, AA loading capacity and encapsulation efficiency (EE) were analyzed. In vitro cytocompatibility was evaluated in fibroblast L-929 cells using the PrestoBlue assay. Single-dose toxicity was studied using rats. HA-pNIPAM nanogels at a 4.88% grafting degree showed reversible thermo-responsive behavior. All nanogel formulations could significantly increase AA water solubility and the stability was higher in nanogels prepared with high polymer concentrations over 180 days. The cell culture study showed that 12.5 µM AA in nanogel formulations was considered non-toxic to the L-929 cells; however, a dose-dependent cytotoxic effect was observed at higher AA-loaded concentrations. In vivo study proved the non-toxic effect of AA loaded in HA-pNIPAM nanogels compared with the control. Taken together, HA-pNIPAM nanogel is a promising biocompatible delivery system both in vitro and in vivo for hydrophobic AA molecules.

Preparation and optimization of controlled release nanoparticles containing cefixime using Central Composite design: An attempt to enrich its antimicrobial activity

Background: Due to the increased resistance against existing antibiotics, research is essential to discover new and alternative ways to control infections induced by resistant pathogens. Objective: The goal of the current scrutinization was to enrich the dissolution rate and antibacterial property of cefixime (CEF) orally. Methods: To achieve the desired results, chitosan nanoparticles (NPs) containing CEF were fabricated using the ionic gelation method. Central Composite design has been applied to get the optimal formulation for the delivery of CEF. The effect of three variables such as the concentration of chitosan, tripolyphosphate, and tween 80 on the characteristics of NPs was evaluated. Results: The optimized NPs were a relatively monodispersed size distribution with an average diameter of 193 nm and a zeta potential of about 11 mV. The scanning tunneling microscope confirmed the size of NPs. The surface morphology of NPs was observed by scanning electron microscopy. The calorimetric analysis indicated the amorphous state of cefixime in the formulation. The dissolution rate of NPs in aqueous media was acceptable and the model of release kinetic for CEF from NPs followed the Peppas model. The potency of CEF in NPs against various types of bacteria was hopefully efficient. The ex- vivo release study demonstrated higher penetration of NPs from the rat intestine compared to free drug. The cell culture study showed the safety of the optimized formulation. Conclusion: It was concluded that CLN could be considered as a prospering system for the controlled delivery of CEF with advantaging its antibacterial effectiveness.

Is Quercetin Beneficial for Colon Cancer? A Cell Culture Study, Using the Apoptosis Pathways

Background: Quercetin (QCT) is a dietary flavonoid with many beneficial effects (e.g., antioxidant, antiaging, antidiabetic, antifungal effects, regulation of gastrointestinal motor activity in humans); furthermore, it induces apoptosis, cell cycle arrest, and differentiation. Objective: The apoptotic effects of OCT were investigated on SW480 human colon cancer cell lines in monolayer and spheroid cultures. Methods: Quercetin (40–200 μM) was applied, and inhibitory concentration (IC50) doses were determined for three-time intervals (24, 48, and 72 h). The effective dose was determined and applied for analyses, including staining with BrdU to investigate cell proliferation, terminal deoxynucleotidyl transferase dUTP nick, and labeling (TUNEL) to investigate apoptosis, and apoptosis-inducing factor (AIF) and Caspase-3 to investigate caspase-dependent or independent apoptotic pathways. Results: The effective dose of QCT was determined to be 200 μM and was found to induce apoptosis and inhibit cell proliferation at 24, 48, and 72 h, both in 2D and 3D cultures. Significant increases were observed in both caspase-3 and AIF staining, but cells showed greater caspase-3 staining compared with AIF staining at all time intervals (p<0.05). Conclusion: The QCT treatment groups showed more cell death and less cell growth than the untreated control groups in both 2D and 3D cultures of SW480 cell lines. The results suggest that quercetin induces apoptosis, inhibits cell proliferation, and has a protective role against colon cancer. However, further studies are needed to clarify its mechanism of action.

mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment

Major depressive disorder (MDD) is a severe psychiatric condition with key symptoms of low mood and lack of motivation, joy, and pleasure. Recently, the acid sphingomyelinase (ASM)/ceramide system has been implicated in the pathogenesis of MDD. ASM is a lysosomal glycoprotein that catalyzes the hydrolysis of sphingomyelin, an abundant component of membranes, into the bioactive sphingolipid ceramide, which impacts signaling pathways. ASM activity is inhibited by several common antidepressant drugs. Human and murine studies have confirmed that increased ASM activity and ceramide levels are correlated with MDD. To define a molecular marker for treatment monitoring, we investigated the mRNA expression of SMPD1, which encodes ASM, in primary cell culture models, a mouse study, and a human study with untreated MDD patients before and after antidepressive treatment. Our cell culture study showed that a common antidepressant inhibited ASM activity at the enzymatic level and also at the transcriptional level. In a genetically modified mouse line with depressive-like behavior, Smpd1 mRNA expression in dorsal hippocampal tissue was significantly decreased after treatment with a common antidepressant. The large human study showed that SMPD1 mRNA expression in untreated MDD patients decreased significantly after antidepressive treatment. This translational study shows that SMPD1 mRNA expression could serve as a molecular marker for treatment and adherence monitoring of MDD.

Half-life modeling of basic fibroblast growth factor released from growth factor-eluting polyelectrolyte multilayers

Growth factor-eluting polymer systems have been widely reported to improve cell and tissue outcomes; however, measurements of actual growth factor concentration in cell culture conditions are limited. The problem is compounded by a lack of knowledge of growth factor half-lives, which impedes efforts to determine real-time growth factor concentrations. In this work, the half-life of basic fibroblast growth factor (FGF2) was determined using enzyme linked immunosorbent assay (ELISA). FGF2 release from polyelectrolyte multilayers (PEMs) was measured and the data was fit to a simple degradation model, allowing for the determination of FGF2 concentrations between 2 and 4 days of culture time. After the first hour, the FGF2 concentration for PEMs assembled at pH = 4 ranged from 2.67 ng/mL to 5.76 ng/mL, while for PEMs assembled at pH = 5, the concentration ranged from 0.62 ng/mL to 2.12 ng/mL. CRL-2352 fibroblasts were cultured on PEMs assembled at pH = 4 and pH = 5. After 2 days, the FGF2-eluting PEM conditions showed improved cell count and spreading. After 4 days, only the pH = 4 assembly condition had higher cells counts, while the PEM assembled at pH = 5 and PEM with no FGF2 showed increased spreading. Overall, the half-life model and cell culture study provide optimal concentration ranges for fibroblast proliferation and a framework for understanding how temporal FGF2 concentration may affect other cell types.

3D printed Chitosan Composite Scaffold for Chondrocytes differentiation

: 3D printing plays a crucial role in the development of controlled porous architectures of scaffolds for cartilage tissue regeneration. In the present study, different compositions of chitosan-gelatin-alginate composite scaffolds with controlled porosity and architectures were 3D printed. To obtain the desired scaffold, an in-house 3D paste extruder printer was developed, which is capable of printing porous composite chitosan hydrogel scaffolds of desired architecture layer by layer. Stereolithography (STL) files of 3D models for porous chitosan composite were created using computeraided design (CAD) and printed with a hydrogel flow rate within the range of 0.2-0.25 ml/min. The prepared composite scaffolds were characterized by Fourier transform infrared spectroscopy (FTIR), X-Ray diffraction (XRD), scanning electron microscopy SEM, swelling property, mechanical testing, porosity, etc. In-vitro cell culture study was observed on 3D printed chitosan, gelatin, and alginate hydrogel scaffolds. The prepared scaffolds were highly porous, having optimum porosity, optimal mechanical strength to sustain the cartilage formation. The 3D printed chitosan composite scaffolds supported the differentiation of chondrocytes. The above study is helpful for in-vivo regeneration of cartilage for patients having related cartilage disorders.

Half-Life Modeling of Basic Fibroblast Growth Factor and its Media Concentration from Growth Factor-Eluting Polyelectrolyte Multilayers

Growth factor-eluting polymer systems have been widely reported to improve cell and tissue outcomes; however, measurements of actual growth factor concentration in cell culture conditions are limited. The problem is compounded by a lack of knowledge of growth factor half-lives, which impedes efforts to determine real-time growth factor concentrations. In this work, the half-life of basic fibroblast growth factor (FGF2) was determined using enzyme linked immunosorbent assay (ELISA). FGF2 release from polyelectrolyte multilayers (PEMs) was measured and the data was fit to a simple degradation model, allowing for the determination of FGF2 concentrations between 2 days and 4 days of culture time. After the first hour, the FGF2 concentration for PEMs assembled at pH=4 ranged from 2.67 ng/mL to 5.76 ng/mL, while for PEMs assembled at pH=5, the concentration ranged from 0.62 ng/mL to 2.12 ng/mL. CRL-2352 fibroblasts were cultured on PEMs assembled at pH=4 and pH=5. After 2 days, the FGF2-eluting PEM conditions showed improved cell count and spreading. After 4 days, only the pH=4 assembly condition had higher cells counts, while the PEM assembled at pH=5 and PEM with no FGF2 showed increased spreading. Overall, the half-life model and cell culture study provide optimal concentration ranges for fibroblast proliferation and a framework for understanding how temporal FGF2 concentration may affect other cell types.