Structured hybrid photodetectors using confined conducting polymer nanochannels.

We design and fabricate hybrid organic inorganic perovskite photodetectors that utilize hole transport layer poly(3,4-ethylene dioxythiophene):poly (styrenesulfonate) PEDOT:PSS confined in alumina nanocylinders. This structural asymmetry in the device where the alumina nanopore template is partially filled with PEDOT:PSS provides features that improve certain device characteristics. The leakage component of the current in such devices is considerably suppressed, resulting in enhanced responsivity and detectivity. The funneling aspect of the photogenerated charge carrier transit ultimately leads to fast detectors as compared to conventional perovskite detectors.

Assessment of soil yeasts Papiliotrema laurentii S-08 and Saitozyma podzolica S-77 for plant growth promotion and biocontrol of Fusarium wilt of brinjal.

AIM: This study aimed to determine the efficacy of the soil yeasts Papiliotrema laurentii S-08 and Saitozyma podzolica S-77 for plant growth promotion (PGP) and biocontrol of wilt disease in brinjal plants while applying yeasts individually or as a consortium in pot experiments. METHODS AND RESULTS: The yeasts were tested for various PGP characteristics and antagonistic activity against the phytopathogen Fusarium oxysporum f. sp. melongenae. Both the yeast isolates demonstrated some PGP attributes as well as inhibited the growth of the phytopathogen. A gas chromatography-mass spectrometry analysis of the yeast metabolites revealed the presence of several antifungal compounds. The pot experiment performed under nursery conditions showed that applying these yeasts, individually or in consortium, decreased the percent disease incidence in brinjal seedlings while significantly enhancing their growth parameters. CONCLUSION: Papiliotrema laurentii S-08 and S. podzolica S-77 can be used in brinjal plants as plant growth promoters and also as biocontrol agents against the brinjal wilt disease.

A Unique Case of Plunging Dermoid Cyst in an Elderly Male: A Case Report.

Dermoid cysts are the least commonly occurring developmental cysts in the oral and maxillofacial region. They may be congenital or acquired and are seen as asymptomatic swellings that are slow and progressive. It is very difficult to differentiate plunging ranulas from plunging dermoid cysts as both of them have very similar clinical features. However, since both entities have different treatment strategies, it is important to differentiate one from the other. A 57-year-old male patient reported to the Department of Oral Medicine and Radiology with a large swelling in the submental region. To the best of our knowledge, the present case report is the first one showing such an extensive lesion of plunging dermoid cyst mimicking plunging ranula in an elderly male patient. The report mainly focuses on the diagnostic challenges faced to reach the final diagnosis.

Evaluating single-cell variability in proteasomal decay.

Gene expression is a stochastic process that leads to variability in mRNA and protein abundances even within an isogenic population of cells grown in the same environment. This variation, often called gene-expression noise, has typically been attributed to transcriptional and translational processes while ignoring the contributions of protein decay variability across cells. Here we estimate the single-cell protein decay rates of two degron GFPs in Saccharomyces cerevisiae using time-lapse microscopy. We find substantial cell-to-cell variability in the decay rates of the degron GFPs. We evaluate cellular features that explain the variability in the proteasomal decay and find that the amount of 20s catalytic beta subunit of the proteasome marginally explains the observed variability in the degron GFP half-lives. We propose alternate hypotheses that might explain the observed variability in the decay of the two degron GFPs. Overall, our study highlights the importance of studying the kinetics of the decay process at single-cell resolution and that decay rates vary at the single-cell level, and that the decay process is stochastic. A complex model of decay dynamics must be included when modeling stochastic gene expression to estimate gene expression noise.

Ordered and disordered microstructures of nanoconfined conducting polymers.

We probe the microstructural differences of conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) derivatives under geometrical nanoconfinement using a high-resolution electron microscopy (HRTEM) technique. Highly ordered domains of poly(3,4-ethylenedioxythiophene):tosylate PEDOT:Tos, which is polymerized within alumina nanochannels, are observed. These features are in contrast to those of the polymer blend poly(3,4-ethylene dioxythiophene):poly(styrenesulfonate) PEDOT:PSS inserted into the nanopores. The extent of the order-disorder parameter in terms of surface crystallization and the number of ordered domains of the long-chain polymers strongly depends on the dopant environment, processing conditions and structural confinement. Atomic force spectroscopy of individual PEDOT nanochannels highlights counterion-dependent surface adhesive factors. The molecular dynamics (MD) simulation of these systems reveals similar polymer chain configurations and the resulting morphology.

Intramolecular Hydroarylation of Arenes via Imidazole-Directed C-H Activation in Aqueous Methanol Using Rhodium(III) as the Catalyst and Mechanistic Study.

A mild and greener approach for intramolecular regioselective hydroarylation is described for the efficient and elegant preparation of a number of dihydrobenzofurans and dihydrobenzo[b]thiophenes using imidazole as a directing group and Rh(III) as a catalyst. Moreover, the protocol may be extended to the formation of indoline and chromane derivatives. Deuterium scrambling experiments and characterization of isolated rhodacycle intermediate were explored to understand the mechanism in a better way.

Low-level laser therapy in the management of muscle fatigue caused after long Endodontic procedure.

Background: The masticatory muscles may undergo fatigue due to prolonged mouth opening during the endodontic procedures. Low-level laser can be used to treat muscle fatigue due its capacity to produce reactive oxygen species and improve function of mitochondria. Aim: To determine the effectiveness of low-level laser therapy in the management of masticatory muscle fatigue caused after long endodontic procedure under Local anesthesia. Material and Methods: 44 patients complaining of reduced mouth opening and pain while mouth opening, after long endodontic therapy were considered for the study and were randomly allocated into study and control group. In the study group, low-level laser was applied while patients of control group didn't receive any therapy. In the study group, Visual analogue scale (VAS) score of pain was taken after endodontic therapy, immediately after laser therapy and 4 hours after endodontic therapy. Mouth opening of the patients was measured, before and after endodontic procedure and immediately after laser therapy. In the control group, VAS score of pain was recorded immediately after endodontic therapy and 4 hours after endodontic therapy. Statistical analysis used: ANOVA test and un-paired t-test was used for the data analysis. Results: When both groups were compared, a statistically significant (P=0.0000) reduction with fatigue was found. Conclusions: The low-level laser can be a useful procedure immediately post long endodontic procedure causing masticatory muscle fatigue. Hence, this therapy can be considered as an add-on therapeutic procedure along with prolonged endodontic appointments to relieve the patient from the discomfort. Key words:Muscle fatigue, Masticatory muscles, Low-level laser therapy.

IMP1/IGF2BP1 in human colorectal cancer extracellular vesicles.

Colorectal cancer (CRC) is a leading cause of cancer-related death. There is an urgent need for new methods of early CRC detection and monitoring to improve patient outcomes. Extracellular vesicles (EVs) are secreted, lipid-bilayer bound, nanoparticles that carry biological cargo throughout the body and in turn exhibit cancer-related biomarker potential. RNA binding proteins (RBPs) are posttranscriptional regulators of gene expression that may provide a link between host cell gene expression and EV phenotypes. Insulin-like growth factor 2 RNA binding protein 1 (IGF2BP1/IMP1) is an RBP that is highly expressed in CRC with higher levels of expression correlating with poor prognosis. IMP1 binds and potently regulates tumor-associated transcripts that may impact CRC EV phenotypes. Our objective was to test whether IMP1 expression levels impact EV secretion and/or cargo. We used RNA sequencing, in vitro CRC cell lines, ex vivo colonoid models, and xenograft mice to test the hypothesis that IMP1 influences EV secretion and/or cargo in human CRC. Our data demonstrate that IMP1 modulates the RNA expression of transcripts associated with extracellular vesicle pathway regulation, but it has no effect on EV secretion levels in vitro or in vivo. Rather, IMP1 appears to affect EV regulation by directly entering EVs in a transformation-dependent manner. These findings suggest that IMP1 has the ability to shape EV cargo in human CRC, which could serve as a diagnostic/prognostic circulating tumor biomarker.NEW & NOTEWORTHY This work demonstrates that the RNA binding protein IGF2BP1/IMP1 alters the transcript profile of colorectal cancer cell (CRC) mRNAs from extracellular vesicle (EV) pathways. IMP1 does not alter EV production or secretion in vitro or in vivo, but rather enters CRC cells where it may further impact EV cargo. Our work shows that IMP1 has the ability to shape EV cargo in human CRC, which could serve as a diagnostic/prognostic circulating tumor biomarker.

Development of an Interferon-Gamma Release Assay (IGRA) to Aid Diagnosis of Histoplasmosis.

Establishing diagnosis of latent and active histoplasmosis is challenging. Interferon gamma-release assays (IGRAs) may provide evidence of latent and active infection. An enzyme-linked immunospot (ELISpot) assay was developed using yeast cell lysate (YCL) antigen prepared from a representative North American Histoplasma capsulatum strain. Assay parameters were optimized by measuring responses in healthy volunteers with and without Histoplasma infection. Assay performance as an aid for diagnosing histoplasmosis was assessed in a prospective cohort of 88 people with suspected or confirmed infection, and 44 healthy controls enrolled in two centers in North America (2013 to 2018). Antigen specificity of IFN-γ release was demonstrated using ELISpot and enzyme-linked immunosorbent assay (ELISA). Antigen-evoked, single-cell mRNA expression by memory T cells was shown using flow cytometry. The area under the receiver operating characteristic curve (AUC) was estimated at 0.89 (95% confidence interval [CI]: 78.5% to 99.9%). At optimal cutoff, sensitivity was 77.2% (95% CI: 54.6% to 92.2%) and specificity was 100% (95% CI: 89.7% to 100%). Sixteen of 44 healthy volunteers (36.4%) from a region of hyperendemicity had positive responses, suggesting detection of previously unrecognized (latent) infection. The ELISpot assay is sensitive and specific as an aid to diagnose H. capsulatum infection and disease, supporting proof of concept and further development.

Short-term consumption of alcohol (vodka) mixed with energy drink (AMED) attenuated alcohol-induced cerebral capillary disturbances and neuroinflammation in adult wild-type mice.

Background: The ingestion of combinatory Alcohol Mixed with Energy Drink (AMED) beverages continues to increase markedly, particularly among young adults. Some studies suggest detrimental health effects related to the combination of alcohol with energy drink formulations; however, the consumption of AMED has not been investigated in context of the cerebral microvasculature or neuroinflammation. We hypothesized that cerebral capillary integrity and glial cells are particularly vulnerable to the combination of AMED.Methods:12-week old wild-type C57BL/6J mice were orally gavaged with either vehicle (water), alcohol (vodka), an energy drink (MotherTM), or a combination AMED, daily for five days. Thereafter, mice were sacrificed, blood alcohol concentrations were analysed and cryosections of brain specimens were subjected to confocal immunofluorescent analysis for measures of cerebral capillary integrity via immunoglobulin G (IgG), and markers of neuroinflammation, ionized-calcium-binding-adaptor-molecule 1 (Iba1) and Glial-Fibrillary-Acidic-Protein (GFAP). Proinflammatory cytokines, IL-2, IL-17A, IFN-ϒ, and anti-inflammatory cytokines, IL-4, IL-6 and IL-10, were also measured in serum.Results: Consistent with previous studies, cerebral capillary dysfunction and astroglial cell activation were markedly greater in the alcohol-only group (AO); however, the AO-induced effects were profoundly attenuated with the AMED combination. Mice maintained on AO and AMED interventions exhibited a moderate increase in microglial recruitment. There were no significant changes in pro-inflammatory nor anti-inflammatory cytokines in ED or AMED treated mice.Conclusion: This study suggests that paradoxically the acute detrimental effects of alcohol on cerebral capillary integrity and astrogliosis are counteracted with the co-provision of an ED, rich in caffeine and taurine and containing B-group vitamins.

Nonsurgical Management of Oral Mucocele Occurring on a Rare Site.

Mucocele is a common salivary gland lesion which most commonly occurs on the lower lip. Several treatment options are available for its elimination with surgery being the most commonly used method. A 49-year-old male presented with a small, round, painless swelling on the left buccal mucosa since 6 months. A clinical diagnosis of oral mucocele on the left buccal mucosa was made. Due to the inaccessibility of the posterior buccal mucosa region, sclerotherapy with sodium tetradecyl sulfate was planned. The patient did not show any obvious reduction in the size of swelling after 1 week of therapy. Therefore, a second injection was planned. After another 1 week, complete resolution of the lesion was seen with no complications. No recurrence of the lesion has been seen after 6 months of therapy. Due to the various drawbacks of surgical management of oral mucocele, sclerotherapy can be an effective alternative.

Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

Mechanical-biological treatment of municipal solid waste: Case study of 100 TPD Goa plant, India.

A long-term feasibility analysis of a 100 ton per day mechanical biological treatment (MBT) plant for municipal solid waste (MSW) valorization and material and energy recovery was carried out. It involves the material recovery and segregation stage (MRSS), organic extraction (pulping), thermophilic anaerobic digestion (AD), composting, effluent treatment plant (ETP), and biogas genset stages producing: 11.90% recyclables, 33% refused derived fuel (RDF), 5% compost of total waste received, 70 m3/day recyclable water and 0.435 MWh/day electricity. The biogas and methane yield were 0.535 and 0.350 m3/kg VSadded (avg.), respectively, with 40% VS removal (avg total solids (TS) 10%). Less than 3% (inert) of total waste received was subjected to landfill disposal. The MBT plant's revenue generation is 995 US$ per day/148 tons ($ 6.72/ton) waste processed. The gross OPEX is 24 US$/ton making the net OPEX of 17 US$/ton (minus revenue), which could be considered as the excellent OPEX for MSW based MBT plants as per global benchmarks. Further, local usage of RDF can significantly reduce the OPEX to 14 US$/ton, as almost 16% of the OPEX goes towards RDF disposal to cement companies located at a distance of 200-500 km from the MBT plant site. As per LCA study, the total GHG emissions have been calculated to be -25.68 tons CO2 eq./100 tons MSW. The negative emissions result from the export of electricity, compost, and RDF as well as recycling of paper and plastic products. Our study presents a cutting-edge scenario of all-inclusive recycling, recovery, and reuse loop of MSW direly required for accomplishing a circular economy.

Epidemiology and diagnosis, environmental resources quality and socio-economic perspectives for COVID-19 pandemic.

The COVID-19 pandemic caused by SARS-CoV-2 has emerged as a global issue of concern for public health, environment and socio-economic setup. This review addresses several aspects of epidemiology, and pathogenesis, environmental resource quality (air quality, hazardous waste management, and wastewater surveillance issues), and socio-economic issues worldwide. The accelerated research activity in the development of diagnostic kits for SARS-CoV-2 is in progress for the rapid sequencing of various strains of SARS-CoV-2. A notable reduction in air pollutants (NO2 and PM2.5) has been observed worldwide, but high air polluted cities showed intense mortalities in COVID-19 affected areas. The use of health safety equipment halted transportation, and work-from-home policy drastically impacted the quantity of solid and hazardous wastes management services. Wastewater appeared as another mode of enteric transmission of SARS-CoV-2. Thus, wastewater-based surveillance could act as a mode of the data source to track the virus's community spread. The pandemic also had a substantial socio-economic impact (health budget, industrial manufacturing, job loss, and unemployment) and further aggravated the countries' economic burden.

Polyphenol Honokiol and Flavone 2',3',4'-Trihydroxyflavone Differentially Interact with α-Synuclein at Distinct Phases of Aggregation.

The association between protein aggregation and neurodegenerative diseases such as Parkinson's disease continues to be well interrogated but poorly elucidated at a mechanistic level. Nevertheless, the formation of amyloid fibrils from the destabilization and misfolding of native proteins is a molecular hallmark of disease. Consequently, there is ongoing demand for the identification and development of small molecules which prevent fibril formation. This study comprehensively assesses the inhibitory properties of two small molecules, the lignan polyphenol honokiol and the flavonoid 2',3',4'-trihydroxyflavone, in preventing α-synuclein fibrilization. The data shows that honokiol does not prevent α-synuclein fibril elongation, while 2',3',4'-trihydroxyflavone is effective at inhibiting fibril elongation and induces oligomer formation (for both wild-type α-synuclein and the disease-associated A53T mutation). Moreover, the exposed hydrophobicity of α-synuclein fibrils is reduced in the presence of 2',3',4'-trihydroxyflavone, whereas the addition of honokiol did not reduce the hydrophobicity of fibrils. In addition, ion mobility-mass spectrometry revealed that the conformation of α-synuclein wild-type and A53T monomers after disassembly is restored to a nonaggregation-prone state upon 2',3',4'-trihydroxyflavone treatment. Collectively, this study shows that the mechanisms by which these polyphenols and flavonoids prevent fibril formation are distinct by their interactions at various phases of the fibril-forming pathway. Furthermore, this study highlights how thorough biophysical interrogation of the interaction is required for understanding the ability of inhibitors to prevent protein aggregation associated with disease.

Small molecule diketone flavorants diacetyl and 2,3-pentanedione promote neurotoxicity but inhibit amyloid ß aggregation.

We investigated the effects of the small molecule flavorants diacetyl, 2,3-pentanedione and acetoin on neuronal cell viability and ß amyloid aggregation and morphology. Two neuroblastoma cell lines, SH-SY5Y and Neuro 2a (N2a) were exposed to diacetyl, 2,3-pentanedione and acetoin, while Thioflavin T fluorescence kinetics and transmission electron microscopy were used to assess effects on Aß1-42 fibril and aggregate formation and morphology respectively. Diacetyl was intrinsically toxic to both SH-SY5Y and N2a cells, with time and concentration-dependent reductions in cell viability occurring over 24 h and 48 h incubation periods. 2.3-Pentanedione evoked a similar concentration-dependent loss of cell viability in N2a cells at 48 h, but exhibited lessened toxicity in SH-SY5Y cells over 24 h, and minimal loss of cell viability by 48 h. Diacetyl inhibited Aß1-42 aggregation kinetics, reduced aggregate and fibril density and rendered Aß1-42 into amorphous small aggregates. 2,3-Pentanedione also reduced overall aggregate formation, but to a lesser extent than diacetyl and retaining the presence of a meshwork of Aß1-42 aggregates and fibrils. Acetoin was innocuous to neuronal cells and did not alter Aß1-42 fibril density or morphology. These findings highlight the intrinsic neurotoxicity of small molecule diketone flavorants. While providing further insight into their molecular interactions with amyloidogenic proteins, the neurotoxicity of such flavorants is a significant finding and warrants further investigation.

Exploring the Structural Diversity in Inhibitors of α-Synuclein Amyloidogenic Folding, Aggregation, and Neurotoxicity.

Aggregation of α-Synuclein (αS) protein to amyloid fibrils is a neuropathological hallmark of Parkinson's disease (PD). Growing evidence suggests that extracellular αS aggregation plays a pivotal role in neurodegeneration found in PD in addition to the intracellular αS aggregates in Lewy bodies (LB). Here, we identified and compared a diverse set of molecules capable of mitigating protein aggregation and exogenous toxicity of αSA53T, a more aggregation-prone αS mutant found in familial PD. For the first time, we investigated the αS anti-amyloid activity of semi-synthetic flavonoid 2', 3', 4' trihydroxyflavone or 2-D08, which was compared with natural flavones myricetin and transilitin, as well as such structurally diverse polyphenols as honokiol and punicalagin. Additionally, two novel synthetic compounds with a dibenzyl imidazolidine scaffold, Compound 1 and Compound 2, were also investigated as they exhibited favorable binding with αSA53T. All seven compounds inhibited αSA53T aggregation as demonstrated by Thioflavin T fluorescence assays, with modified fibril morphology observed by transmission electron microscopy. Ion mobility-mass spectrometry (IM-MS) was used to monitor the structural conversion of native αSA53T into amyloidogenic conformations and all seven compounds preserved the native unfolded conformations of αSA53T following 48 h incubation. The presence of each test compound in a 1:2 molar ratio was also shown to inhibit the neurotoxicity of preincubated αSA53T using phaeochromocytoma (PC12) cell viability assays. Among the seven tested compounds 2-D08, honokiol, and the synthetic Compound 2 demonstrated the highest inhibition of aggregation, coupled with neuroprotection from preincubated αSA53T in vitro. Molecular docking predicted that all compounds bound near the lysine-rich region of the N-terminus of αSA53T, where the flavonoids and honokiol predominantly interacted with Lys 23. Overall, these findings highlight that (i) restricted vicinal trihydroxylation in the flavone B-ring is more effective in stabilizing the native αS conformations, thus blocking amyloidogenic aggregation, than dihydroxylation aggregation in both A and B-ring, and (ii) honokiol, punicalagin, and the synthetic imidazolidine Compound 2 also inhibit αS amyloidogenic aggregation by stabilizing its native conformations. This diverse set of molecules acting on a singular pathological target with predicted binding to αSA53T in the folding-prone N-terminal region may contribute toward novel drug-design for PD.

Structure-activity relationships for flavone interactions with amyloid ß reveal a novel anti-aggregatory and neuroprotective effect of 2',3',4'-trihydroxyflavone (2-D08).

Naturally-occurring flavonoids have well documented anti-aggregatory and neuroprotective properties against the hallmark toxic protein in Alzheimer's disease, amyloid ß (Aß). However the extensive diversity of flavonoids has limited the insight into the precise structure-activity relationships that confer such bioactive properties against the Aß protein. In the present study we have characterised the Aß binding properties, anti-aggregatory and neuroprotective effects of a discreet set of flavones, including the recently described novel protein sumoylation inhibitor 2',3',4'-trihydroxyflavone (2-D08). Quercetin, transilitin, jaceosidin, nobiletin and 2-D08 were incubated with human Aß1-42 for 48h in vitro and effects on Aß fibrillisation kinetics and morphology measured using Thioflavin T (ThT) and electron microscopy respectively, in addition to effects on neuronal PC12 cell viability. Of the flavones studied, only quercetin, transilitin and 2-D08 significantly inhibited Aß1-42 aggregation and toxicity in PC12 cells. Of those, 2-D08 was the most effective inhibitor. The strong anti-amyloid activity of 2-D08 indicates that extensive hydroxylation in the B ring is the most important determinant of activity against ß amyloid within the flavone scaffold. The lack of efficacy of jaceosidin and nobiletin indicate that extension of B ring hydroxylation with methoxyl groups result in an incremental loss of anti-fibrillar and neuroprotective activity, highlighting the constraint to vicinal hydroxyl groups in the B ring for effective inhibition of aggregation. These findings reveal further structural insights into anti-amyloid bioactivity of flavonoids in addition to a novel and efficacious anti-aggregatory and neuroprotective effect of the semi-synthetic flavone and sumoylation inhibitor 2',3',4'-trihydroxyflavone (2-D08). Such modified flavones may facilitate drug development targeting multiple pathways in neurodegenerative disease.

Identification of dibenzyl imidazolidine and triazole acetamide derivatives through virtual screening targeting amyloid beta aggregation and neurotoxicity in PC12 cells.

Aggregation and neurotoxicity of amyloid ß (Aß) protein is a hallmark characteristic of Alzheimer's disease (AD). In this study we compared the anti-aggregatory and neuroprotective effects of five synthetic compounds against Aß protein; four of which possessed a five membered heterocycle ring scaffold (two dibenzyl phenyl imidazolidines and two triazole sulfanyl acetamides) and one with a fused five membered heterocycle (benzoxazole) ring, selected thorough virtual screening from ZINC database. Molecular docking of their optimized structures was used to study Aß binding characteristics. As predicted from molecular docking, strong steric binding of imidazolidines and H-bonding of both triazoles to Aß were translated into anti Aß aggregation properties. Subsequent transmission electron microscopy (TEM) was used to assess their effects on Aß1-42 fibril formation. Four compounds variably altered morphology of Aß fibrils from long, intertwined fibrils to short, loose structures. Thioflavin T assay of Aß fibrillisation kinetics demonstrated that one imidazolidine and both triazole compounds inhibited Aß aggregation. Rat pheochromocytoma (PC12) cells were exposed to Aß1-42, alone and in combination with the heterocyclic compounds to assess neuroprotective effects. Aß1-42-evoked loss of neuronal cell viability was significantly attenuated in the presence of both imidazolidine compounds, while the triazole acetamides and benzoxazole compound were toxic to PC12 cells. These findings highlight the Aß anti-aggregative and neuroprotective propensity of a dibenzyl phenyl imidazolidine scaffold (Compound 1 and 2). While the triazole sulfanyl acetamide scaffold also possessed Aß anti-aggregation properties, they also demonstrated significant intrinsic neurotoxicity. Overall, the predictive efficacy of in silico methods enables the identification of novel imidazolidines that act both as inhibitors of Aß aggregation and neurotoxicity, and may provide a further platform for the development of novel Alzheimer's disease-modifying pharmacotherapies.

Quantum Chemical and Docking Insights into Bioavailability Enhancement of Curcumin by Piperine in Pepper.

We combine quantum chemical and molecular docking techniques to provide new insights into how piperine molecule in various forms of pepper enhances bioavailability of a number of drugs including curcumin in turmeric for which it increases its bioavailability by a 20-fold. We have carried out docking studies of quantum chemically optimized piperine structure binding to curcumin, CYP3A4 in cytochrome P450, p-Glycoprotein and UDP-glucuronosyltransferase (UGT), the enzyme responsible for glucuronosylation, which increases the solubility of curcumin. All of these studies establish that piperine binds to multiple sites on the enzymes and also intercalates with curcumin forming a hydrogen bonded complex with curcumin. The conjugated network of double bonds and the presence of multiple charge centers of piperine offer optimal binding sites for piperine to bind to enzymes such as UDP-GDH, UGT, and CYP3A4. Piperine competes for curcumin's intermolecular hydrogen bonding and its stacking propensity by hydrogen bonding with enolic proton of curcumin. This facilitates its metabolic transport, thereby increasing its bioavailability both through intercalation into curcumin layers through intermolecular hydrogen bonding, and by inhibiting enzymes that cause glucuronosylation of curcumin.