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.

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.

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.

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.

Bioactive polyphenol interactions with ß amyloid: a comparison of binding modelling, effects on fibril and aggregate formation and neuroprotective capacity.

In this study we compared the effects of a diverse set of natural polyphenolics ligands on in silico interactive modelling, in vitro anti-aggregative properties and neuronal toxicity of ß amyloid. The ß amyloid-binding characteristics of optimised structural conformations of polyphenols with ascribed neuroprotective actions including punicalagin, myricetin, luteolin and honokiol were determined in silico. Thioflavin T and transmission electron microscopy were used to assess in vitro inhibitory effects of these polyphenols on Aß1-42 fibril and aggregation formation. Phaeochromocytoma (PC12) cells were exposed to Aß1-42, alone and in combination with test concentrations of each polyphenol (100 µM) and viability measured using MTT assay. Aß1-42 evoked a concentration-dependent loss of cell viability in PC12 cells, in which all four polyphenols demonstrated significant inhibition of neurotoxicity. While all compounds variably altered the morphology of Aß aggregation, the flavonoids luteolin and myricetin and the lignan honokiol all bound in a similar hydrophobic region of the amyloid pentamer and exerted the most pronounced inhibition of Aß1-42 aggregation. Each of the polyphenols demonstrated neuroprotective effects in PC12 cells exposed to Aß1-42, including punicalagin. These findings highlight some structure-activity insights that can be gleaned into the anti-aggregatory properties of bioactive polyphenols based on modelling of their binding to ß-amyloid, but also serve to highlight the more general cellular neuroprotective nature of such compounds.