Cathepsin D inhibition during neuronal differentiation selectively affects individual proteins instead of overall protein turnover.

Cathepsin D (CTSD) is a lysosomal aspartic protease and its inherited deficiency causes a severe pediatric neurodegenerative disease called neuronal ceroid lipofuscinosis (NCL) type 10. The lysosomal dysfunction in the affected patients leads to accumulation of undigested lysosomal cargo especially in none-dividing cells, such as neurons, resulting in death shortly after birth. To explore which proteins are mainly affected by the lysosomal dysfunction due to CTSD deficiency, Lund human mesencephalic (LUHMES) cells, capable of inducible dopaminergic neuronal differentiation, were treated with Pepstatin A. This inhibitor of "acidic" aspartic proteases caused accumulation of acidic intracellular vesicles in differentiating LUHMES cells. Pulse-chase experiments involving stable isotope labelling with amino acids in cell culture (SILAC) with subsequent mass-spectrometric protein identification and quantification were performed. By this approach, we studied the degradation and synthesis rates of 695 and 680 proteins during early and late neuronal LUHMES differentiation, respectively. Interestingly, lysosomal bulk proteolysis was not altered upon Pepstatin A treatment. Instead, the protease inhibitor selectively changed the turnover of individual proteins. Especially proteins belonging to the mitochondrial energy supply system were differentially degraded during early and late neuronal differentiation indicating a high energy demand as well as stress level in LUHMES cells treated with Pepstatin A.

Polycaprolactone/graphene oxide/acellular matrix nanofibrous scaffolds with antioxidant and promyelinating features for the treatment of peripheral demyelinating diseases.

Peripheral demyelinating diseases entail damage to axons and Schwann cells in the peripheral nervous system. Because of poor prognosis and lack of a cure, this group of diseases has a global impact. The primary underlying cause of these diseases involves the inability of Schwann cells to remyelinate the damaged insulating myelin around axons, resulting in neuronal death over time. In the past decade, extensive research has been directed in the direction of Schwann cells focusing on their physiological and neuroprotective effects on the neurons in the peripheral nervous system. One cause of dysregulation in the remyelinating function of Schwann cells has been associated with oxidative stress. Tissue-engineered biodegradable scaffolds that can stimulate remyelination response in Schwann cells have been proposed as a potential treatment strategy for peripheral demyelinating diseases. However, strategies developed to date primarily focussed on either remyelination or oxidative stress in isolation. Here, we have developed a multifunctional nanofibrous scaffold with material and biochemical cues to tackle both remyelination and oxidative stress in one matrix. We developed a nanofibrous scaffold using polycaprolactone (PCL) as a foundation loaded with antioxidant graphene oxide (GO) and coated this bioscaffold with Schwann cell acellular matrix. In vitro studies revealed both antioxidant and remyelination properties of the developed bioscaffold. Based on the results, the developed multifunctional bioscaffold approach can be a promising biomaterial approach for treating demyelinating diseases.

Enhanced energy storage performance and theoretical studies of 3D cuboidal manganese diselenides embedded with multiwalled carbon nanotubes.

The burst of energy produced from the sustainable energy sources need to be harnessed by energy storage systems. Development of novel and advanced energy storage devices such as supercapacitors discover an enormous future ahead. Recently, hybrid supercapacitors (electric double layer capacitor (EDLC) and pseudocapacitors) trend to be used as energy storage interfaces for their improved efficacy in energy density without altering the power density. In the ongoing workplan, transition metal selenides MnSe2 and its hybrid with multiwalled carbon nanotubes (MWCNTs) are synthesized by a simplistic hydrothermal protocol. Certainly, cubic phases of MnSe2-MWCNT(MS/CNT) manifested superior electrochemical performance in both symmetric and asymmetric full cell configurations in contrast to prestine MnSe2(MS). The asymmetric MS/CNT cell achieved an excellent charge storage capability with an high energy density of 39.45 Wh kg-1 at a power density of 2.25 kW kg-1 maintaining an energy density of 14.5 Wh kg-1 at a high power density of 4.5 kWh kg-1 and also revealed long term stability over 5000 consecutive charge/discharge cycles (capacitance retention of 95.2%). Furthermore, the preferable growth along (200) direction in the presence of MWCNTs favoured in enriching the supercapacitive property of MS. The quantum capacitance of MnSe2surfaces and MS/CNT heterostructure has been estimated using density functional theory simulation to confirm the experimental outcomes. Theoretical investigation simultaneously exposed the contribution of (200) plane of MnSe2 and MWCNTs cultured in enhanced DOS (density of states) near the Fermi level that remarkably promoted the energy storage efficiency of MS/CNT.

Synthesis and evaluation of thiazolidinone-pyrazole conjugates as anticancer and antimicrobial agents.

AIM: To synthesize a series of new thiazolidinone-pyrazole hybrids (5a-o) and assess their anticancer (in vitro and in vivo) and antimicrobial activities. RESULTS: The compounds 5h (against Ehrlich ascites carcinoma cells), 5e and 5i (against the human breast cancer [MDA-MB231] cell line) exhibited potent anticancer activity. All the compounds except 5g and 5e found to be less toxic for the human dermal fibroblast cells. The effective interactions of the compounds in silico with MDM2 exemplified their inhibitory potency. The derivatives also showed moderate antimicrobial activity. CONCLUSION: The halogen atoms on various positions of the N-arylamino ring played an advantageous role in elevating the potency of the molecules. Thus, these conjugates could be used as a lead for further optimization to achieve promising therapeutics.

Rapid 'one-pot' synthesis of a novel benzimidazole-5-carboxylate and its hydrazone derivatives as potential anti-inflammatory and antimicrobial agents.

A novel series of N-arylidene-2-(2,4-dichloro phenyl)-1-propyl-1H-benzo[d] imidazole-5-carbohydrazides having different substitution on the arylidene part were synthesized in good yield. The core nucleus benzimidazole-5-carboxylate (5) was efficiently synthesized by 'one-pot' nitro reductive cyclization reaction between ethyl-3-nitro-4-(propylamino)benzoate and 2,4-dichlorobenzaldehyde using sodium dithionite in dimethylsulfoxide. This 'one-pot' reaction was proceeded very smoothly, in short reaction time with an excellent yield. All the compounds (7a-r) were screened for their in vivo anti-inflammatory and in vitro antimicrobial activity. Most of the compounds exhibited remarkable paw-edema inhibition in the initial one hour of administration indicating the higher potentiality of these molecules. In particular, compounds 7a, 7d, 7f and 7g displayed a high level of carrageenan-induced paw edema inhibition compared to that of indomethacin. Compound 7p exhibited very good antibacterial activity and antifungal activity with a MIC of 3.12 µg/mL against most of the tested organisms. Furthermore, compounds 7d, 7f, 7h and 7p found to be good inhibitors of Aspergillus niger with MIC of 3.12 µg/mL. Cytotoxicity of the potent compounds 7d, 7f and 7p was checked using MDA MB-231 breast cancer cell line and are found to be non toxic at the highest concentration used (i.e., 10 µg/mL).