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Sirtuin 1 (SIRT1), a member of histone deacetylase III family, plays a pivotal role in mediating chemoresistance in several cancers, including breast cancer. However, the molecular mechanism by which the deregulated SIRT1 promotes doxorubicin (Dox) resistance is still elusive. Here, we showed that the cell proliferation rates and invasive properties of MDA-MB-231 breast cancer cells were increased from low- to high-Dox-resistant cells. In agreement, severe combined immunodeficiency disease (SCID) mice bearing labeled MDA-MB-231 high Dox-Res cells showed significantly higher tumor growth, angiogenesis, and metastatic ability than parental MDA-MB-231 cells. Interestingly, the levels of SIRT1 and glutathione (GSH) were positively correlated with the degree of Dox-resistance. Dox-induced SIRT1 promoted NRF2 nuclear translocation with an accompanying increase in the antioxidant response element promotor activity and GSH levels. In contrast, inhibition of SIRT1 by EX527 greatly reversed these events. More so, Dox-resistance-induced pro-proliferative, proangiogenic, and invasive effects were obviated with depletion of either SIRT1 or GSH. Together, Dox-induced SIRT1 promotes dysregulation of redox homeostasis leading to breast cancer chemoresistance, tumor aggressiveness, angiogenesis, and metastasis., (© 2024 Wiley Periodicals LLC.)

Aim: The current study's aim was to evaluate the orthodontic bracket's bond strength employing three different bonding agents on a ceramic crown surface., Materials and Methods: Tooth preparation on 60 permanent maxillary premolar teeth extracted for orthodontic purposes was carried out. Supragingival finishing margins were made for all samples, and ceramic (PFM) crowns were fabricated. Following crown cementation on the prepared samples, they were divided into three experimental groups randomly ( n = 20) as follows: group I: Bracket bonding using Transbond XT bonding agent; group II: Bracket bonding using RelyX TM Unicem bonding agent; and group III: Bracket bonding using Assure Plus bonding agent. A universal testing machine was utilized to conduct the shear bond strength test. Using a stereomicroscope with a 10× magnification, adhesive remnant index scores were also used to assess the adhesive that was remaining on the surfaces. Data was recorded and statistically analyzed., Results: The highest bond strength was found in RelyX TM Unicem bonding agent (19.38 ± 0.84) followed by Transbond XT bonding agent (17.12 ± 1.04) and Assure Plus bonding agent (16.14 ± 1.02). A highly significant difference was found between Transbond XT vs RelyX TM Unicem groups and RelyX TM Unicem vs Assure Plus groups. There was no significant difference found between Transbond XT and Assure Plus ( p > 0.001). Adhesive Remnant Index scores showed that score 1 was higher [7 (35%)] in the Transbond XT bonding agent group. Score 1 was 8 (40%) and score 2 was 6 (30%) in RelyX TM Unicem bonding agent groups and in Assure Plus bonding agent group, score 2 was higher [9 (45%)]., Conclusion: In conclusion, RelyX TM Unicem exhibited superior bond strength with ceramic crowns when compared to Assure Plus and Transbond XT bonding agents., Clinical Significance: One of the most important steps in orthodontic therapy is bonding brackets to the teeth. A high enough and long-lasting bond between brackets and artificial surfaces is necessary for orthodontic treatment to be successful, as is the requirement for a bonding agent with the highest possible binding strength. The necessity for a more dependable process to glue the artificial crown surface has arisen due to the rise in adult patients seeking fixed orthodontic treatment. How to cite this article: Brajendu, Haque I, Sam G, et al. Assessment of the Bond Strength of Orthodontic Bracket on Ceramic Crown Surface Using Three Various Bonding Agents: A Comparative Study. J Contemp Dent Pract 2024;25(8):762-765.

The development and progression of hyperglycemia (HG) and HG-associated atherosclerosis are exacerbated by mitochondrial dysfunction due to dysregulated mitochondria-derived ROS generation. We recently synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and tested its dose-response therapeutic efficacy in mitigating HG-induced atherosclerosis in db/db mice. In comparison to simvastatin and pioglitazone, Mito-Esc administration resulted in a considerable reduction in body weights and improved glucose homeostasis, possibly by reducing hepatic gluconeogenesis, as indicated by a reduction in glycogen content, non-esterified free fatty acids (NEFA) levels, and fructose 1,6-bisphosphatase (FBPase) activity. Interestingly, Mito-Esc treatment, by regulating phospho-IRS and phospho-AKT levels, greatly improved palmitate-induced insulin resistance, resulting in enhanced glucose uptake in adipocytes and HepG2 cells. Also, and importantly, Mito-Esc administration prevented HG-induced atheromatous plaque formation and lipid accumulation in the descending aorta. In addition, Mito-Esc administration inhibited the HG-mediated increase in VACM, ICAM, and MAC3 levels in the aortic tissue, as well as reduced the serum pro-inflammatory cytokines and markers of senescence. In line with this, Mito-Esc significantly inhibited monocyte adherence to human aortic endothelial cells (HAECs) treated with high glucose and reduced high glucose-induced premature senescence in HAECs by activating the AMPK-SIRT1 pathway. In contrast, Mito-Esc failed to regulate high glucose-induced endothelial cell senescence under AMPK/SIRT1-depleted conditions. Together, the therapeutic efficacy of Mito-Esc in the mitigation of hyperglycemia-induced insulin resistance and the associated atherosclerosis is in part mediated by potentiating the AMPK-SIRT1 axis. KEY MESSAGES: Mito-Esc administration significantly mitigates diabetes-induced atherosclerosis. Mito-Esc improves hyperglycemia (HG)-associated insulin resistance. Mito-Esc inhibits HG-induced vascular senescence and inflammation in the aorta. Mito-Esc-mediated activation of the AMPK-SIRT1 axis regulates HG-induced endothelial cell senescence., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Impaired mitochondrial fatty acid β-oxidation (FAO) plays a role in the onset of several age-associated diseases, including atherosclerosis. In the current work, we investigated the efficacies of mitochondria-targeted esculetin (Mito-Esc) and metformin in enhancing FAO in human aortic endothelial cells (HAECs), and its relevance in the delay of cellular senescence and age-associated atherosclerotic plaque formation in Apoe -/- mice. Chronic culturing of HAECs with either Mito-Esc or metformin increased oxygen consumption rates (OCR), and caused delay in senescence features. Conversely, etomoxir (CPT1 inhibitor) reversed Mito-Esc- and metformin-induced OCR, and caused premature endothelial senescence. Interestingly, Mito-Esc, unlike metformin, in the presence of etomoxir failed to preserve OCR. Thereby, underscoring Mito-Esc's exclusive reliance on FAO as an energy source. Mechanistically, chronic culturing of HAECs with either Mito-Esc or metformin led to AMPK activation, increased CPT1 activity, and acetyl-CoA levels along with a concomitant reduction in malonyl-CoA levels, and lipid accumulation. Similar results were observed in Apoe -/- mice aorta and liver tissue with a parallel reduction in age-associated atherosclerotic plaque formation and degeneration of liver with either Mito-Esc or metformin administration. Together, Mito-Esc and metformin by potentiating FAO, may have a role in the delay of cellular senescence by modulating mitochondrial function., Competing Interests: Conflict of Interest The authors declare the following competing financial interest(s): patents and patent applications describing Mito-Esc for its biological properties (with inventors P.S, C.H, G.S, A.S, R.T, and S.K) are assigned to CSIR., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: The current study aimed to assess the efficiency of two desensitizing dentifrices on the management of dental hypersensitivity., Materials and Methods: For the purpose of this investigation, 60 extracted human sound premolar teeth that were removed for orthodontic purposes were collected. On the buccal cervical areas, an inverted-cone bur was used to create cavities that were 2 mm deep and 3 mm wide. The blocks were submerged in 17% ethylenediaminetetraacetic acid (EDTA) for 40 minutes in order to ensure the complete dentin tubule opening. Following preparation, all samples were split into three groups, each containing 20 samples, Group A: Control, Group B: Dentifrice containing calcium sodium phosphosilicate, Group C: Dentifrice containing casein phosphopeptide-amorphous calcium phosphate (CPP-ACP). Scanning electron microscopy (SEM) was used to assess the occlusion of dentinal tubules. One-way analysis of variance (ANOVA) was used to assess the desensitization efficacy of dentifrices. At a p -value less than 0.05, statistical significance was determined., Result: Before application of different dentifrices, the maximum dentinal tubules opened in dentifrice containing CPP-ACP group (4.24 ± 0.10) followed by control group (4.18 ± 0.01) and dentifrice containing calcium sodium phosphosilicate (4.12 ± 0.06). And there was no significant difference between the different dentifrice groups ( p > 0.001). After application of different dentifrices, the highest occlusion of dentinal tubules found in dentifrice containing CPP-ACP group (2.50 ± 0.05) followed by dentifrice containing calcium sodium phosphosilicate (2.84 ± 0.10) and control group (4.02 ± 0.07) and there was a highly significant difference between the different dentifrice groups ( p < 0.001)., Conclusion: On conclusion, dentifrice containing CPP-ACP exhibited the highest level of dentinal tubule occlusion in comparison to the control group and dentifrice containing calcium sodium phosphosilicate., Clinical Significance: Dentinal hypersensitivity (DH) is a condition that is frequently experienced. With variable outcomes, a number of products are utilized in the management of DH. Need is felt in dentistry for a material that chemically reacts, physically occludes and adheres intimately to dentinal tubules to reduce the possibility of its recurrence. How to cite this article: Pulipaka S, Ramanna PK, Samson A, et al. Assessment of the Effectiveness of Desensitizing Dentifrices on Management of Dental Hypersensitivity: An In Vitro Study. J Contemp Dent Pract 2024;25(5):494-497.

Atherosclerosis, in general, is an age-associated cardiovascular disease wherein a progressive decline in mitochondrial function due to aging majorly contributes to the disease development. Mitochondria-derived ROS due to dysregulated endothelial cell function accentuates the progression of atherosclerotic plaque formation. To circumvent this, mitochondrially targeted antioxidants are emerging as potential candidates to combat metabolic abnormalities. Recently, we synthesized an alkyl TPP + tagged esculetin (Mito-Esc), and in the current study, we investigated the therapeutic efficacies of Mito-Esc and metformin, a well-known anti-diabetic drug, in the amelioration of age-associated plaque formation in the aortas of 12 months aged Apoe -/- and 20 months aged C57BL/6 mice, in comparison to young C57BL/6 control mice. Administration of Mito-Esc or metformin significantly reduced age-induced atherosclerotic lesion area, macrophage polarization, vascular inflammation, and senescence. Further, chronic passaging of human aortic endothelial cells (HAEC) with either Mito-Esc or metformin significantly delayed cellular senescence via the activation of the AMPK-SIRT1/SIRT6 axis. Conversely, depletion of either AMPK/SIRT1/SIRT6 caused premature senescence. Consistent with this, Mito-Esc or metformin treatment attenuated NFkB-mediated inflammatory signaling and enhanced ARE-mediated anti-oxidant responses in comparison to late passage control HAECs. Importantly, culturing of HAECs for several passages with either Mito-Esc or metformin significantly improved mitochondrial function. Overall, Mito-Esc and metformin treatments delay age-associated atherosclerosis by regulating vascular senescence via the activation of AMPK-SIRT1/SIRT6 axis., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Mitochondrial dysfunction due to deregulated production of mitochondria-derived ROS is implicated in the development and progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Recently, we synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and investigated its dose-response therapeutic efficacy in mitigating high-fat diet (HFD)-induced NAFLD and NASH in Apoe -/- mice. Mito-Esc administration, compared to simvastatin and pioglitazone, dose-dependently caused a significant reduction in body weight, improved lipid profile, glucose homeostasis, and pro-inflammatory cytokines level. Mito-Esc administration reduced adipose tissue hypertrophy and lipid accumulation presumably by regulating the levels of CD36, PPAR-γ, EBP-α, and their target genes. Mechanistically, Mito-Esc-induced activation of the AMPK1α-SIRT1 axis inhibited pre-adipocyte differentiation. Conversely, Mito-Esc failed to regulate pre-adipocyte differentiation under AMPK/SIRT1 depleted conditions. In parallel, Mito-Esc administration ameliorated HFD-induced steatosis, fibrosis of the liver, and NAFLD-associated atheromatous plaque formation in the aorta. Importantly, Mito-Esc administration inhibited HFD-induced infiltration of macrophages, a marker of steatohepatitis, in the adipose and liver tissues. The results of the in vitro studies showed that Mito-Esc treatment significantly inhibits TGF-β-induced hepatic stellate cell differentiation as well as the fibrotic markers. Consistent with the above observations, Mito-Esc treatment by activating the AMPK-SIRT1 pathway markedly reversed palmitate-induced mitochondrial superoxide production, depolarization of mitochondrial membrane potential, and lipid accumulation in HepG2 cells. Together, the therapeutic efficacy of Mito-Esc in the mitigation of HFD-induced lipotoxicity, and the associated NASH is in part, mediated by potentiating the AMPK-SIRT1 axis., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare the following competing financial interest(s): patents and patent applications describing Mito-Esc for its biological properties (with inventors G. S, S. P, A.S, S.B.A, R.T, and S.K) are assigned to CSIR., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: To demonstrate the suitability of using decellularized SMILE (Small-incision Lenticule Extraction) lenticules for culturing and transplanting the corneal endothelium (CE)., Methods: The SMILE lenticules, obtained during refractive surgery, were decellularized by incubating in CE culture medium and fetal bovine serum. Decellularization was confirmed by hematoxylin and eosin staining, DAPI staining, and gel electrophoresis. The amount of DNA per milligram of dry tissue weight was calculated to quantify the residual nuclear content. The transparency of the decellularized lenticules was determined by calculating the modulation transfer function. Immunostaining for stromal collagens and glycosaminoglycan was performed using specific antibodies. Engineered tissue was constructed by culturing the CE cells on lenticules and staining for ZO-1, Na/K ATPase, and N-cadherin. The functionality of the engineered tissues was assessed by transplanting them onto edematous human donor corneas and perfusing for 10 days ex-vivo ., Results: The residual DNA per milligram of dry tissue weight was found to be significantly reduced ( p  < 0.0001) in serum (0.255 µg/mg) and Opti-MEM (0.140 µg/mg) when compared to fresh lenticules (3.9 µg/mg). Decellularization did not alter the arrangement of the collagen fibers or the transparency of the lenticules. CE cells attached and matured to express ZO-1, Na/K ATPase, and N-cadherin at two weeks after seeding. The engineered tissue upon transplantation significantly reduced the corneal edema ( p  < 0.05) and the transplanted cells remained intact on the SMILE lenticule post-transplantation., Conclusion: This study demonstrates the suitability of using SMILE lenticules decellularized using a simple, chemical-free method for engineering the corneal endothelium for transplantation.

A direct access to unsymmetrical and symmetrical multi-substituted pyridines has been accomplished via iron-catalysed [3+3] annulation of oxime acetates with enaminones. This protocol is featured by easily available starting materials, no requirement of expensive additives and ligands, operational simplicity, and good tolerance with diverse functional groups., (© 2022 Wiley-VCH GmbH.)

DOT1L, a specific H3K79 methyltransferase, has a tumour-promoting role in various cancers, including triple-negative breast cancer (TNBC). However, the molecular mechanism by which the deregulated DOT1L promotes cancer progression is unclear. Herein, we show that a significantly higher basal level of DOTL1 strongly correlates with MTDH, an oncogene, in clinical TNBC patient cohorts and mediates TNBC progression by enhancing MTDH-induced angiogenesis. In parallel, severe combined immunodeficiency mice-bearing MDA-MB-231 cells with MTDH-Wt or MTDHΔ7 (spliced isoform of MTDH) overexpression constructs showed enhanced blood vessel formations at the tumour site in comparison with control groups. Selective inhibition of DOT1L by EPZ004777, a specific DOT1L inhibitor, or siDOT1L, significantly impaired MTDH-induced proliferation, invasion and angiogenic markers expression in TNBC cells. ChIP assay revealed that Dot1L promotes MTDH-Wt/Δ7 transcription by increasing H3K79me3 levels on its promoter. Dot1L depletion reversed this effect. Mechanistically, DOT1L-induced MTDH caused enhanced nuclear factor kappa B (NF-κB) occupancy on the hypoxia-inducible factor1α (HIF1α) promoter and increased its transcription, leading to elevated levels of proangiogenic mediators in TNBC cells. Moreover, the condition media obtained from MDA-MB-231 cells stably expressing either MTDH-Wt or MTDHΔ7 treated with EPZ004777 or Bay-11-7082 (NF-κB inhibitor) or FM19G11 (HIF1α inhibitor) significantly inhibited MTDH-induced tube formation in human umbilical vein endothelial cells, rat aortic ring sprouting and vessel formations by chick chorioallantoic membrane assay mimicking physiological angiogenic vasculature. Collectively, our findings reveal a novel epigenetic regulation of MTDH by DOTL1, which drives angiogenesis, and that the therapeutic disruption of the DOT1L-MTDH-NF-κB-HIF1α axis may have usefulness in the management of TNBC., (© 2022 Federation of European Biochemical Societies.)

Background and Aims: Age is a dominant and independent risk factor for the development of atherosclerosis, a major cardiovascular disease, and if left untreated leads to myocardial infarction and death. Mitochondria-targeted anti-oxidants are evolving as a new class of compounds that can alter the pathophysiology of age-related diseases, including atherosclerosis, where mitochondrial dysfunction plays a critical role in disease progression., Methods: We recently synthesized an alkyl TPP + -tagged esculetin (mitochondria-targeted esculetin or Mito-Esc). Apoe -/- mice were chronically (14 months) administered with Mito-Esc to investigate its efficacy in the mitigation of atherosclerosis in the setting of aging. We monitored BP, and performed various biochemical assays, histopathology, immunohistochemistry, inflammatory factors, qPCR, and Western blotting. Simultaneously, human aortic endothelial cells (HAECs) were used as a model system to study the mechanistic aspects., Results: A chronic low-dose administration of Mito-Esc to Apoe -/- mice greatly prevented alterations in lipid profile, blood pressure, and atherosclerotic plaque formation in the setting of aging. Mito-Esc administration significantly reduced vascular senescence and pro-inflammatory cytokines levels and prevented dysregulation of mitochondrial biogenesis markers in aortic tissue. Further, Mito-Esc treatment prevented replicative and stress-induced premature senescence (SIPS) in HAEC. Importantly, Mito-Esc treatment delayed endothelial cell senescence by increasing human telomerase reverse transcriptase (hTERT) levels via SIRT1 activation. Moreover, Mito-Esc treatment by altering miR-19b and miR-30c via a SIRT1 activation significantly inhibited the increase in PAI-1 levels in HAEC as well as in the serum of Apoe -/- mice. In addition, Mito-Esc treatment improved mitochondrial function in late passage (aged) HAECs by enhancing the oxygen consumption rate (OCR). Furthermore, Mito-Esc administration counteracted the decline in GSH and nitrite levels in Apoe -/- mice and in HAECs., Conclusions: Overall, Mito-Esc alleviates atherosclerosis in the setting of aging by delaying vascular senescence and pro-inflammatory processes, and by improving mitochondrial biogenesis and function., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This work describes the highly selective and sensitive robust analytical method (gas chromatography) for the qualitative and quantitative analysis of commonly used residual solvents (like methanol, ethanol, acetonitrile, dichloromethane, methyl tert-butyl ether, n-hexane, 1-propanol, ethyl acetate, tetrahydrofuran, N,N-diisopropylethylamine (DIPEA) and dimethylformamide), in an active pharmaceuticals ingredients. The developed method was optimized with good resolution (>1.9 between close eluting solvents) and a shorter run time (20 min). All the solvents were separated using GC column DB-624, 30-m length, 0.32-mm diameter, 1.8-μm particle size, nitrogen as a carrier gas and recorded the signals using flame ionization detector (FID). Further, analytical method validation has been performed for the developed analytical method and the validation results demonstrated its routine application for the determination of residual solvents content by GC-head space (HS). The practical application was demonstrated by the suitable API batch analysis (having sample Con. 40 mg/mL). The present developed method has more advantages than the other methods for the qualitative and quantitative applications, such as shorter runtime, selective for multiple solvents (11 organic solvents) analysis at a time, highly sensitive at ppm levels. This GC-HS method could be used for the qualitative and quantitative determination of the residual solvents content in APIs., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)