Computational Design, Synthesis, and Bioevaluation of 2-(Pyrimidin-4-yl)oxazole-4-carboxamide Derivatives: Dual Inhibition of EGFRWT and EGFRT790M with ADMET Profiling.

The ongoing research in cancer treatment underscores the significance of dual epidermal growth factor receptor (EGFR) kinase inhibitors targeting both mutant and wild-type variants. In this study, employing in silico fragment-based drug design (FBDD) and computational analysis, we have successfully developed a novel chemical series of 2-(pyrimidin-4-yl)oxazole-4-carboxamide (16a-j) derivatives designed as dual EGFR kinase inhibitors. A comparative in vitro anticancer profile of the newly synthesized compounds (16a-j) was tested against a panel of five human cancer cell lines like prostate cancer (PC3 & DU-145), lung cancer (A549), human liver cancer (HEPG2), and breast cancer (MDA-MB-468) by employing MTT method. In this experiment a well-known anticancer agent, Etoposide was used as positive control. Most of the derivatives demonstrated significant cytotoxicity, ranging from excellent to moderate levels. The IC50 values for the synthesized compounds observed between 0.10 ± 0.052 to 9.83 ± 5.96 µM, while the positive control exhibited a range of 1.97 ± 0.45 µM to 3.08 ± 0.135 µM. These results indicate that the synthesized compounds demonstrate higher cytotoxic potency in comparison to the reference compound. Furthermore, all these compounds underwent screening against normal Vero cell lines to assess their cytotoxicity. In each case, the observed cytotoxicity values (IC50) were higher than 22 µM, affirming the compounds selectivity for cancer cell lines. Among the compounds investigated, three compounds (16a, 16e, and 16i) exhibited notable cytotoxicity, while two compounds (16g and 16h) demonstrated exceptional cytotoxicity. The selectivity index of the tested compounds indicates a pronounced preference for targeting cancer cell lines over normal cells. Furthermore, all the compounds 16a-j underwent assessment for their EGFR kinase inhibitory activity against both EGFRWT and mutated EGFRT790M. The results unveiled the potential eligibility of this new series of compounds as effective EGFR inhibitors. Moreover, compound 16h underwent additional testing for cell cycle analysis, revealing its capability to arrest the cell cycle in the G2/M phase and induce apoptosis at the IC50 concentration.

Repurposing of approved antivirals against dengue virus serotypes: an in silico and in vitro mechanistic study.

Dengue is an emerging, mosquito-borne viral disease of international public health concern. Dengue is endemic in more than 100 countries across the world. However, there are no clinically approved antivirals for its cure. Drug repurposing proves to be an efficient alternative to conventional drug discovery approaches in this regard, as approved drugs with an established safety profile are tested for new indications, which circumvents several time-consuming experiments. In the present study, eight approved RNA-dependent RNA polymerase inhibitors of Hepatitis C virus were virtually screened against the Dengue virus polymerase protein, and their antiviral activity was assessed in vitro. Schrödinger software was used for in silico screening, where the compounds were passed through several hierarchical filters. Among the eight compounds, dasabuvir was finally selected for in vitro cytotoxicity and antiviral screening. Cytotoxicity profiling of dasabuvir in Vero cells revealed changes in cellular morphology, cell aggregation, and detachment at 50 µM. Based on these results, four noncytotoxic concentrations of dasabuvir (0.1, 0.25, 0.5, and 1 µM) were selected for antiviral screening against DENV-2 under three experimental conditions: pre-infection, co-infection, and post-infection treatment, by plaque reduction assay. Viral plaques were reduced significantly (p < 0.05) in the co-infection and post-infection treatment regimens; however, no reduction was observed in the pretreatment group. This indicated a possible interference of dasabuvir with NS5 RdRp, as seen from in silico interaction studies, translating into a reduction in virus plaques. Such studies reiterate the usefulness of drug repurposing as a viable strategy in antiviral drug discovery. In this drug repurposing study, dasabuvir, a known anti-hepatitis C drug, was selected through virtual screening and assessed for its anti-dengue activity.

Awakening sleeper cells: a narrative review on bacterial magic spot synthetases as potential drug targets to overcome persistence.

Magic spot synthetases are emerging targets to overcome persistence caused by stringent response. The 'stringent response' is a bacterial stress survival mechanism, which results in the accumulation of alarmones (also called Magic spots) leading to the formation of dormant persister cells. These 'sleeper cells' evade antibiotic treatment and could result in relapse of infection. This review broadly investigates the phenomenon of stringent response and persistence, and specifically discusses the distribution, classification, and nomenclature of proteins such as Rel/SpoT homologs (RSH), responsible for alarmone synthesis. The authors further explain the relevance of RSH as potential drug targets to break the dormancy of persister cells commonly seen in biofilms. One of the significant factors that initiate alarmone synthesis is nutrient deficiency. In a starved condition, ribosome-associated RSH detects deacylated tRNA and initiates alarmone synthesis. Accumulation of alarmones has a considerable effect on bacterial physiology, virulence, biofilm formation, and persister cell formation. Preventing alarmone synthesis by inhibiting RSH responsible for alarmone synthesis will prevent or reduce persister cells' formation. Magic spot synthetases are thus potential targets that could be explored to overcome persistence seen in biofilms.

Pro-atherogenic actions of signal transducer and activator of transcription 1 serine 727 phosphorylation in LDL receptor deficient mice via modulation of plaque inflammation.

Atherosclerosis is a chronic inflammatory disorder of the vasculature regulated by cytokines. We have previously shown that extracellular signal-regulated kinase-1/2 (ERK1/2) plays an important role in serine 727 phosphorylation of signal transducer and activator of transcription-1 (STAT1) transactivation domain, which is required for maximal interferon-γ signaling, and the regulation of modified LDL uptake by macrophages in vitro. Unfortunately, the roles of ERK1/2 and STAT1 serine 727 phosphorylation in atherosclerosis are poorly understood and were investigated using ERK1 deficient mice (ERK2 knockout mice die in utero) and STAT1 knock-in mice (serine 727 replaced by alanine; STAT1 S727A). Mouse Atherosclerosis RT² Profiler PCR Array analysis showed that ERK1 deficiency and STAT1 S727A modification produced significant changes in the expression of 18 and 49 genes, respectively, in bone marrow-derived macrophages, with 17 common regulated genes that included those that play key roles in inflammation and cell migration. Indeed, ERK1 deficiency and STAT1 S727A modification attenuated chemokine-driven migration of macrophages with the former also impacting proliferation and the latter phagocytosis. In LDL receptor deficient mice fed a high fat diet, both ERK1 deficiency and STAT1 S727A modification produced significant reduction in plaque lipid content, albeit at different time points. The STAT1 S727A modification additionally caused a significant reduction in plaque content of macrophages and CD3 T cells and diet-induced cardiac hypertrophy index. In addition, there was a significant increase in plasma IL-2 levels and a trend toward increase in plasma IL-5 levels. These studies demonstrate important roles of STAT1 S727 phosphorylation in particular in the regulation of atherosclerosis-associated macrophage processes in vitro together with plaque lipid content and inflammation in vivo, and support further assessment of its therapeutical potential.

Ultrasound assisted one-pot synthesis of rosuvastatin based novel azaindole derivatives via coupling-cyclization strategy under Pd/Cu-catalysis: Their evaluation as potential cytotoxic agents.

Addressing the increasing incidences of cancer worldwide along with the multifaceted problem of drug resistance via development of new anticancer agents has become an essential goal. Due to the known cytotoxic effects and reported Akt inhibitory potential of azaindoles we designed a new framework incorporating the structural features of rosuvastatin and 5- or 7-azaindole. The framework was used to construct a library of small molecules for further pharmacological evaluation. The design was supported by the docking studies of two representative molecules in silico. A one-pot sonochemical approach was established for the synthesis of these rosuvastatin based azaindoles that involved the coupling-cyclization of a rosuvastatin derived terminal alkyne with appropriate 3-iodopyridine derivatives under Pd/Cu-catalysis. When tested using an MTT assay, some of the synthesized compounds showed desirable cytotoxic effects against three cancer cell lines e.g. HCT 116, Hep G2 and PA-1 but no significant effects against the non-cancerous HEK cell line. According to the SAR the 5-azaindole ring appeared to be marginally better than the 7-azaindole whereas the activity was varied with the variation of sulfonamide moiety attached to the N-1 atom of the azaindole ring. Among all the groups present in the sulfonamide moiety the p-MeC6H4 group appeared to be most effective in terms of activity. While 3b and 5b were identified as initial hit molecules the compound 5b (in addition to 3b) also showed significant inhibition of Akt1 in vitro that was reflected by its strong interaction with Akt1 in silico (with the docking score -11.7 kcal/mol) involving two H-bonding interactions with Ser7 and Asp439 residues. Further, a reasonable ADME was predicted for 5bin silico. Being a potent inhibitor (MIA Paca-2 IC50 = 18.79 ± 0.17 nM) and with NOAEL (No Observed Adverse Effect Level) > 100 µM in Zebrafish, 5b emerged as a promising compound.

Design, synthesis, biological evaluation, and in silico studies of 2-aminobenzothiazole derivatives as potent PI3Kα inhibitors.

A new series of 2-aminobenzothiazole derivatives was designed, synthesized and evaluated for their anticancer activity against the MCF7, MDAMB-231, and HepG2 cancer cell lines. All synthesized derivatives (8a-8n) demonstrated moderate to high anticancer activity against the tested cell lines. As the most potent compound in the series, compound 8i displayed excellent inhibitory potency with an IC50 value of 6.34 µM and compound 8m displayed an IC50 value of 8.30 µM against the MCF7 cell line compared to the standard drug HS-173 (IC50 = 10.25 µM). PI3K enzyme activity assays demonstrated that compound 8i is highly selective against PI3Kα, with an IC50 value of 1.03 nM. Wound healing assays and cell cycle analysis of compounds 8i and 8m revealed that both compounds suppressed the migration of MCF7 cells and induce cell cycle arrest in the S phase. In the cell death assay, compound 8i was revealed to induce apoptosis in a dose-dependent pattern; further Western blot assays revealed that compound 8i obviously decreases the levels of the antiapoptotic proteins Bcl-xL and Mcl-1. Downregulation of the expression of p-Akt confirmed the PI3K inhibitory activity of compound 8i. The molecular docking and molecular dynamics simulation studies performed were found in agreement with the PI3Kα inhibitory activity assessments performed experimentally.

An appraisal of anticancer activity with structure-activity relationship of quinazoline and quinazolinone analogues through EGFR and VEGFR inhibition: A review.

Cancer is one of the leading causes of death. Globally a huge number of deaths and new incidences are reported annually. Heterocyclic compounds have been proved to be very effective in the treatment of different types of cancer. Among different heterocyclic scaffolds, quinazoline and quinazolinone core were found versatile and interesting with many biological activities. In the discovery of novel anticancer agents, the Quinazoline core is very effective. The FDA has approved more than 20 drugs as an anticancer bearing quinazoline or quinazolinone core in the last two decades. One prime example is Dacomitinib, which was newly approved for non-small-cell lung carcinoma treatment in 2018. These drugs work by different pathways to prevent the spread of cancer cell progression, including inhibition of different kinases, tubulin, kinesin spindle protein, and so forth. This review presented recent developments of quinazoline/quinazolinone scaffold bearing derivatives as anticancer agents acting as epidermal growth factor receptor (EGFR) vascular endothelial growth factor receptor (VEGFR), and dual EGFR/VEGFR inhibitors.

Synthesis, biological evaluation, and in silico studies of indole-tethered pyrazoline derivatives as anticancer agents targeting topoisomerase IIα.

We herein report a new series of indole-tethered pyrazoline derivatives as potent anticancer agents. A total of 12 compounds were designed and synthesized by conventional as well as microwave-irradiated synthesis methods. The latter method results in a significant reduction in the duration of reaction along with improved yields. All synthesized derivatives (7a-7l) were evaluated for their cytotoxic activity against A431, HeLa, and MDAMB-231 cell lines. Compounds 7a and 7b were found most potent in the series and demonstrated an IC50 value of 3.17 and 5.16 µM against the A431 cell line, respectively, compared to the standard drug doxorubicin. Compounds 7a and 7b significantly suppress colony formation, migration, and S phase cell cycle arrest of A431 cells. Furthermore, compound 7a regulated the expression of apoptotic proteins causing the downregulation of procaspase 3/9, antiapoptotic protein Bcl-xL, and upregulation of proapoptotic protein Bax in a dose-dependent manner. Topoisomerase enzyme inhibition assay confirmed that compounds 7a and 7b can significantly inhibit topoisomerase IIα. In vivo oral acute toxicity of compounds 7a and 7b revealed that both compounds are safe compared to doxorubicin; cardiomyopathy studies showed normal architecture of cardiomyocytes and myofibrils. In addition, molecular docking studies revealed the possible interaction of compounds 7a and 7b within the active binding site of the topoisomerase enzyme. The 100 ns molecular dynamic simulation of compounds 7a and 7b proved that both compounds validate all screening parameters.

Neuromodulatory potential of phenylpropanoids; para-methoxycinnamic acid and ethyl-p-methoxycinnamate on aluminum-induced memory deficit in rats.

Para-methoxycinnamic acid (PMCA) and Ethyl-p-methoxycinnamate (EPMC) are reported to possess neuroprotective effect in reversing an acute memory deficit. However, there is a dearth of evidence for their therapeutic effect in chronic memory deficit. Thus, there is a scope to study these derivatives against the chronic model of cognitive dysfunction. The present study was aimed to determine the cognitive enhancing activity of PMCA and EPMC in aluminum-induced chronic dementia. Cognitive enhancing property of PMCA and EPMC was assessed using Morris water maze by analyzing spatial memory parameters such as escape latency, D-quadrant latency, and island entries. To find a possible mechanism, the effect of test compounds on altered acetylcholinesterase (AChE) activity and oxidative stress was determined in the hippocampus and frontal cortex of rats. Docking interaction of these derivatives with acetylcholinesterase enzyme and glutamate receptors was also studied. Treatment with PMCA and EPMC showed a significant improvement in spatial memory markers and altered hippocampal AChE activity in rats with cognitive dysfunction. The implication of hippocampal and cortical oxidative stress in memory impairment was confirmed with decreased catalase/increased thiobarbituric acid reactive substances (TBARS) in rats. PMCA and EPMC reversed the oxidative stress in the brain by negatively affecting TBARS levels. Against depleted catalase levels, PMCA was more effective than EPMC in raising the depleted catalase levels. In silico analysis revealed poor affinity of EPMC and PMCA with AChE enzyme and glutamate receptor. To conclude, PMCA and EPMC exerted cognitive enhancing property independent of direct AChE and glutamate receptor inhibition.

A standards-based approach for linking as-planned to as-fabricated product data.

The digital thread links disparate systems across the product lifecycle to support data curation and information cultivation and enable data-driven applications, e.g., digital twin. Realizing the digital thread requires the integration of semantically-rich, open standards to facilitate the dynamic creation of context based on multiple viewpoints. This research develops such an approach to link as-planned (ISO 6983) to as-fabricated (MTConnect) product data using dynamic time warping. Applying this approach to a production part enabled the designer to make a more optimal decision from the perspective of the product lifecycle that would have otherwise been challenging to identify.

Design, Synthesis and Biological Evaluation of Oxindole-Based Chalcones as Small-Molecule Inhibitors of Melanogenic Tyrosinase.

The enzyme tyrosinase regulates melanogenesis and skin hyperpigmentation by converting L-3,4-dihydroxyphenylalanine (L-DOPA) into dopaquinone, a key step in the melanin biosynthesis. The present work deals with design and synthesis of various oxindole-based chalcones as monophenolase and diphenolase activity inhibitors of tyrosinase. Among the screened compounds, 4-hydroxy-3-methoxybenzylidene moiety bearing chalcone (7) prepared by one pot reaction of oxindole and vanillin displayed the highest activity against tyrosinase with IC50s of 63.37 and 59.71 µM in monophenolase and diphenolase activity assays, respectively. In molecular docking studies, chalcone 7 also showed the highest binding affinity towards the enzyme tyrosinase while exhibiting the lowest estimated free energy of binding, among all the ligands docked.

Design, synthesis, and biological evaluation of oxindole derivatives as antidepressive agents.

The 3-substituted oxindole derivatives were designed, synthesized, and evaluated for antidepressant activity by employing forced swimming test, tail suspension test, and MAO-A inhibition assay. Results of biological studies revealed that the majority of compounds exhibited potent to moderately potent activity and among them, 12 displayed potency comparable to that of the imipramine with %DID of 37.95 and 44.84 in the FST and TST, respectively. At the same time, imipramine showed %DID of 43.62 and 50.64 in the FST and TST, correspondingly. In the MAO-A inhibition assay, 12 showed an IC50 of 18.27 µmol, whereas the reference drug moclobemide displayed an IC50 of 13.1 µmol. The SAR study disclosed that the presence of bromo atom at the phenyl/furanyl or thienyl moiety in the oxindole derivatives was critical for the antidepressant activity.

The Impact of Red Beetroot Products on Glycemic Profiles: A Systematic Review of Human Evidence.

PURPOSE OF REVIEW: Low-glycemic diets are crucial, particularly for individuals with diet-related diseases such as obesity and diabetes. Therefore, observing the impact of multiple forms of red beetroot-based products on the glycemic profiles of humans under various health conditions has arguably become significant due to beetroot's high fiber content, antioxidants, inorganic nitrates, etc., which this review aims to summarize. RECENT FINDINGS: The relevant articles published between 2000 and 2022 were obtained from PubMed, Scopus, and ScienceDirect by following the PRISMA-P 2020 statement. This systematic review included 18 randomized controlled trials (RCTs), one non-randomized clinical trial (non-RCT), and one quasi-experimental (QE) study, and they covered different health conditions, e.g., type-2 diabetes mellitus (T2DM), obesity, hypertension, etc. The studies produced conflicting results, likely due to differences in the study design, dosage, duration, and population. The risk of bias in most of the RCTs and QE studies included in the review was assessed as low or moderate, and only one non-RCT was assessed as having a high risk of bias. Red beetroot may help maintain the blood sugar levels of humans under different health conditions. However, the existing results on beetroot's potential for glycemic management are unclear due to varied outcomes across studies. Further intervention studies with standardized protocols and diverse participant groups are necessary to assess the role of beetroot products in regulating blood sugar levels before making a definitive judgment.

Computational design, synthesis, and assessment of 3-(4-(4-(1,3,4-oxadiazol-2-yl)-1H-imidazol-2-yl)phenyl)-1,2,4-oxadiazole derivatives as effective epidermal growth factor receptor inhibitors: a prospective strategy for anticancer therapy.

The epidermal growth factor receptor (EGFR) enzyme plays a critical role in governing the cell cycle, positioning it as a promising target for the development of anticancer drugs. In this study, we endeavored to design and synthesize innovative EGFR inhibitors with potential applications in anticancer therapy. A novel series of compounds, namely 3-(4-(4-(1,3,4-oxadiazol-2-yl)-1H-imidazol-2-yl)phenyl)-1,2,4-oxadiazoles (30a-j), were meticulously designed using FBDD efforts and synthesized. The synthesized compounds underwent thorough characterization using 1HNMR, 13CNMR, HRMS, and mass spectrum analyses. The in vitro anticancer activities of the newly developed compounds (30a-j) were evaluated against four human cancer cell lines such as prostate cancer (PC3 & DU-145), lung cancer (A549), and liver cancer (HEPG2) using the MTT method. The results, expressed as IC50 values, demonstrated significant anticancer activity for several compounds, with five compounds (30a, 30b, 30c, 30i, and 30j) exhibiting superior potency compared to the established anticancer drug etoposide. Notably, compound 30a emerged as the most promising compound, displaying potent cytotoxicity. We also conducted a screening of the compounds on the normal Vero cell line, revealing a pronounced selectivity of the compounds against cancer cell lines, with no observable impact on the normal cell lines. Moreover, the synthesized compounds were investigated for their impact on enzyme EGFR activity. The findings revealed a robust inhibitory effect against the EGFR wild-type enzyme and a 10-fold inferior potency against the mutant form of EGFR. This observation underscores the potential of the new derivatives as effective EGFRWT inhibitors with substantial anticancer efficacy. Further studies, including cell cycle analysis and apoptosis assays in HEPG2 cell lines, revealed cell cycle arrest at G1/G0 and G2 phases. We also evaluated the potential influence of compound 30a on the EGFR pathway using western blot analysis, revealing a significant inhibition of EGFR autophosphorylation in HEPG2 cells. In conclusion, our findings highlight the promise of these novel compounds as potent EGFR inhibitors, encouraging further investigation and development for the creation of novel and effective anticancer therapeutics.

Correction: computational design, synthesis, and assessment of 3-(4-(4-(1,3,4-oxadiazol-2-yl)-1H-imidazol-2-yl)phenyl)-1,2,4-oxadiazole derivatives as effective epidermal growth factor receptor inhibitors: a prospective strategy for anticancer therapy.

[This corrects the article DOI: 10.1039/D4MD00055B.].

Geriatric Oral Health and Quality of Life Among the Indigenous Irula Tribes of Tamil Nadu.

OBJECTIVES: This study aims to assess the oral health-related quality of life (OHRQoL) among the Irula tribes and to know the factors influencing quality of life among the elderly irula tribes of Tamil Nadu. METHODS: This cross-sectional study was conducted in the Northern district of Tamil Nadu, including 486 Irula individuals aged 65 and above. Participants were selected using a multistage sampling method. Data were collected through a structured questionnaire, including the Geriatric Oral Health Assessment Index (GOHAI) to evaluate OHRQoL. The study tool covered demographics, medical history, and oral health issues. Data analysis was performed using SPSS version 23, with logistic regression applied to account for confounders. RESULTS: The sample primarily consisted of individuals aged 65-69 years (55.6%), with a predominance of females (76.3%). The majority were Hindu (94.9%) and lived in nuclear families (88.3%). Educational levels were low, with 66.5% being illiterate. Most participants were agricultural laborers (64.6%) and had low monthly incomes. GOHAI results revealed that many respondents faced significant oral health challenges, including difficulties with eating, speaking, and discomfort. Multivariate analysis showed that educational level significantly affected OHRQoL, with higher education correlating with better quality of life. Arthritis was associated with poorer OHRQoL, while other health conditions did not show significant impacts. CONCLUSION: The study highlights severe oral health issues among the Irula community, with significant physical and psychological impacts. Educational attainment plays a crucial role in OHRQoL, while arthritis notably affects quality of life. The findings emphasize the need for targeted oral health interventions and increased awareness in tribal communities to improve overall health outcomes. Further research in larger populations is necessary to comprehensively understand and address geriatric oral health needs.

Recent Progress in the Oral Delivery of Therapeutic Peptides and Proteins: Overview of Pharmaceutical Strategies to Overcome Absorption Hurdles.

Purpose: Proteins and peptides have secured a place as excellent therapeutic moieties on account of their high selectivity and efficacy. However due to oral absorption limitations, current formulations are mostly delivered parenterally. Oral delivery of peptides and proteins (PPs) can be considered the need of the hour due to the immense benefits of this route. This review aims to critically examine and summarize the innovations and mechanisms involved in oral delivery of peptide and protein drugs. Methods: Comprehensive literature search was undertaken, spanning the early development to the current state of the art, using online search tools (PubMed, Google Scholar, ScienceDirect and Scopus). Results: Research in oral delivery of proteins and peptides has a rich history and the development of biologics has encouraged additional research effort in recent decades. Enzyme hydrolysis and inadequate permeation into intestinal mucosa are the major causes that result in limited oral absorption of biologics. Pharmaceutical and technological strategies including use of absorption enhancers, enzyme inhibition, chemical modification (PEGylation, pro-drug approach, peptidomimetics, glycosylation), particulate delivery (polymeric nanoparticles, liposomes, micelles, microspheres), site-specific delivery in the gastrointestinal tract (GIT), membrane transporters, novel approaches (self-nanoemulsifying drug delivery systems, Eligen technology, Peptelligence, self-assembling bubble carrier approach, luminal unfolding microneedle injector, microneedles) and lymphatic targeting, are discussed. Limitations of these strategies and possible innovations for improving oral bioavailability of protein and peptide drugs are discussed. Conclusion: This review underlines the application of oral route for peptide and protein delivery, which can direct the formulation scientist for better exploitation of this route.

Depressive symptoms and their correlates among predoctoral dental students in the United States.

OBJECTIVE: To investigate the prevalence of self-reported depressive symptoms among predoctoral dental students in the United States and examine potential correlates. METHODS: A survey was emailed to all 66 dental schools in the United States, inviting them to distribute it to their predoctoral students. Depressive symptoms were assessed using the Patient Health Questionnaire-9. Data collection occurred from February to April 2020. Multivariable ordinal logistic regression was used to assess associations between demographic variables and depressive symptom severity category, adjusting for potential confounding. RESULTS: Of an estimated 25,000 predoctoral dental students at the 66 schools, 631 students from 21 schools completed the survey. A total of 24.1% were categorized as having minimal or no depressive symptoms, 33.6% as having mild depressive symptoms, and 42.3% as having moderate, moderately severe, or severe depressive symptoms. Gender (p = 0.015) and race/ethnicity (p = 0.002) were significant predictors of severity, adjusting for other variables. Students identifying as female had higher odds of self-reporting greater depressive severity symptoms compared with students identifying as male. Students identifying as African American/Black (non-Hispanic) and Asian/Pacific Islander had higher odds of self-reporting greater depressive severity symptoms compared with students identifying as White. CONCLUSION: There is evidence of a high prevalence of depressive symptoms among predoctoral dental students in the United States. Demographic variables may be risk indicators within this population. Approaches to reduce depressive symptoms among US predoctoral dental students are needed.