Biological evaluation of levofloxacin and its thionated derivatives: antioxidant activity, aldehyde dehydrogenase enzyme inhibition, and cytotoxicity on A549 cell line.

Levofloxacin (LVX) is among the fluoroquinolones antibiotics that has also been studied in vitro and in vivo for its anticancer effects. In this study, we used LVX and novel LVX thionated derivatives; compounds 2 and 3, to evaluate their antioxidant activity, aldehyde dehydrogenase (ALDH) enzymes activity inhibition, and anticancer activity. Combination treatments with doxorubicin (DOX) were investigated as well. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to determine the antioxidant activity. The NADH fluorescence spectrophotometric activity assay was used to determine the ALDH inhibitory effects. Resazurin dye method was applied for cell viability assays. Molecular Operating Environment software was used for the molecular docking experiments. Compared to ascorbic acid, DPPH assay showed that compound 3 had the highest antioxidant activity among the tested compounds with approximately 35% scavenging activity. On ALDH enzymes, compound 3 showed a significant ALDH activity inhibition compared to compound 2 at 200 µM. The IC50 values for the tested compounds were approximately 100 µM on A549 cell line, a non-small cell lung cancer (NSCLC) cell line. However, significant enhancement of cytotoxicity and reduction of IC50 values were observed by combining DOX and synergism was achieved with LVX with a combination index value of 0.4. The molecular docking test showed a minimum binding energy with a good affinity for compound 3 towards ALDH enzymes. Thionated LVX derivatives, may be repurposed for NSCLC therapy in combination with DOX, taking into account the antioxidant activity, ALDH activity inhibition, and the molecular docking results of compound 3.

Investigating Carvedilol's Repurposing for the Treatment of Non-Small Cell Lung Cancer via Aldehyde Dehydrogenase Activity Modulation in the Presence of ß-Adrenergic Agonists.

Repurposing existing drugs appears to be a potential solution for addressing the challenges in the treatment of non-small cell lung cancer (NSCLC). ß-adrenoceptor antagonist drugs (ß-blockers) have tumor-inhibiting effects, making them promising candidates for potential NSCLC treatment. This study investigates the anticancer potential of a subset of ß-blockers in NSCLC cell lines; A549 and H1299. Additionally, it investigates the underlying mechanism behind ß-blockers' anticancer effect by influencing a potential novel target named aldehyde dehydrogenase (ALDH). The MTT assay assessed ß-blockers' cytotoxicity on both cell lines, while Western blot and NADH fluorescence assays evaluated their influence on ALDH protein expression and activity. Carvedilol (CAR) was the most effective blocker in reducing cell survival of A549 and H1299 with IC50 of 18 µM and 13.7 µM, respectively. Significantly, CAR led to a 50% reduction in ALDH expression and 80% decrease in ALDH activity in A549 cells, especially when combined with ß-agonists, in comparison to the control. This effect might be attributed to ß-agonist blockade or an alternative pathway. This novel finding adds to our understanding of CAR's multifaceted anticancer properties, implying that combining CAR with ß-agonists could be a useful strategy for lung cancer treatment.

In Vitro Evaluation of ALDH1A3-Affinic Compounds on Breast and Prostate Cancer Cell Lines as Single Treatments and in Combination with Doxorubicin.

Aldehyde dehydrogenase (ALDH) enzymes are involved in the growth and development of several tissues, including cancer cells. It has been reported that targeting the ALDH family, including the ALDH1A subfamily, enhances cancer treatment outcomes. Therefore, we aimed to investigate the cytotoxicity of ALDH1A3-affinic compounds that have been recently discovered by our group, on breast (MCF7 and MDA-MB-231) and prostate (PC-3) cancer cell lines. These compounds were investigated on the selected cell lines as single treatments and in combination with doxorubicin (DOX). Results showed that the combination treatment experiments of the selective ALDH1A3 inhibitors (compounds 15 and 16) at variable concentrations with DOX resulted in significant increases in the cytotoxic effect on the MCF7 cell line for compound 15, and to a lesser extent for compound 16 on the PC-3 cell line, compared to DOX alone. The activity of compounds 15 and 16 as single treatments on all cell lines was found to be non-cytotoxic. Therefore, our findings showed that the investigated compounds have a promising potential to target cancer cells, possibly via an ALDH-related pathway, and sensitize them to DOX treatment.

Design and Synthesis of Thionated Levofloxacin: Insights into a New Generation of Quinolones with Potential Therapeutic and Analytical Applications.

Levofloxacin is a widely used fluoroquinolone in several infectious diseases. The structure-activity relationship of levofloxacin has been studied. However, the effect of changing the carbonyl into thiocarbonyl of levofloxacin has not been investigated up to the date of this report. In this work, levofloxacin structure was slightly modified by making a thionated form (compound 3), which was investigated for its antibacterial activity, biocompatibility, and cytotoxicity, as well as spectroscopic properties. The antibacterial susceptibility testing against five different bacteria showed promising minimum inhibitory concentrations (MICs), particularly against B. spizizenii and E. coli, with an MIC value of 1.9 µM against both bacteria, and 7.8 µM against P. mirabilis. The molecular docking experiment showed similar binding interactions of both levofloxacin and compound 3 with the active site residues of topoisomerase IV. The biocompatibility and cytotoxicity results revealed that compound 3 was more biocompatible with normal cells and more cytotoxic against cancer cells, compared to levofloxacin. Interestingly, compound 3 also showed an excitation profile with a distinctive absorption peak at λmax 404 nm. Overall, our results suggest that the thionation of quinolones may provide a successful approach toward a new generation with enhanced pharmacokinetic and safety profiles and overall activity as potential antibacterial agents.

In vitro radiosensitization of breast cancer with hypoxia-activated prodrugs.

KP167 is a novel hypoxia-activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy of KP167 and its parental comparator, AQ4N, were evaluated in 2D and 3D cultures of luminal and triple negative breast cancer (TNBC) cell lines and compared against DNA damage repair inhibitors. 2D normoxic treatment with the DNA repair inhibitors, Olaparib or KU-55933 caused, as expected, substantial radiosensitization (sensitiser enhancement ratio, SER0.01 of 1.60-3.42). KP167 induced greater radiosensitization in TNBC (SER0.01 2.53 in MDAMB-231, 2.28 in MDAMB-468, 4.55 in MDAMB-436) and luminal spheroids (SER0.01 1.46 in MCF-7 and 1.76 in T47D cells) compared with AQ4N. Significant radiosensitization was also obtained using KP167 and AQ4N in 2D normoxia. Although hypoxia induced radioresistance, radiosensitization by KP167 was still greater under 2D hypoxia, yielding SER0.01 of 1.56-2.37 compared with AQ4N SER0.01 of 1.13-1.94. Such data show KP167 as a promising single agent and potent radiosensitiser of both normoxic and hypoxic breast cancer cells, with greater efficacy in TNBCs.

Expansion of the 4-(Diethylamino)benzaldehyde Scaffold to Explore the Impact on Aldehyde Dehydrogenase Activity and Antiproliferative Activity in Prostate Cancer.

Aldehyde dehydrogenases (ALDHs) are overexpressed in various tumor types including prostate cancer and considered a potential target for therapeutic intervention. 4-(Diethylamino)benzaldehyde (DEAB) has been extensively reported as a pan-inhibitor of ALDH isoforms, and here, we report on the synthesis, ALDH isoform selectivity, and cellular potencies in prostate cancer cells of 40 DEAB analogues; three analogues (14, 15, and 16) showed potent inhibitory activity against ALDH1A3, and two analogues (18 and 19) showed potent inhibitory activity against ALDH3A1. Significantly, 16 analogues displayed increased cytotoxicity (IC50 = 10-200 µM) compared with DEAB (>200 µM) against three different prostate cancer cell lines. Analogues 14 and 18 were more potent than DEAB against patient-derived primary prostate tumor epithelial cells, as single agents or in combination treatment with docetaxel. In conclusion, our study supports the use of DEAB as an ALDH inhibitor but also reveals closely related analogues with increased selectivity and potency.

Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors.

Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Therefore, finding selective inhibitors against ALDH1A3 could result in new treatment options for cancer treatment. In this study, ALDH1A3-selective candidates were designed based on the physiological substrate resemblance, synthesized and investigated for ALDH1A1, ALDH1A3 and ALDH3A1 selectivity and cytotoxicity using ALDH-positive A549 and ALDH-negative H1299 cells. Two compounds (ABMM-15 and ABMM-16), with a benzyloxybenzaldehyde scaffold, were found to be the most potent and selective inhibitors for ALDH1A3, with IC50 values of 0.23 and 1.29 µM, respectively. The results also show no significant cytotoxicity for ABMM-15 and ABMM-16 on either cell line. However, a few other candidates (ABMM-6, ABMM-24, ABMM-32) showed considerable cytotoxicity on H1299 cells, when compared to A549 cells, with IC50 values of 14.0, 13.7 and 13.0 µM, respectively. The computational study supported the experimental results and suggested a good binding for ABMM-15 and ABMM-16 to the ALDH1A3 isoform. From the obtained results, it can be concluded that benzyloxybenzaldehyde might be considered a promising scaffold for further drug discovery aimed at exploiting ALDH1A3 for therapeutic intervention.

Exploration of [2 + 2 + 2] cyclotrimerisation methodology to prepare tetrahydroisoquinoline-based compounds with potential aldo-keto reductase 1C3 target affinity.

Tetrahydroisoquinoline (THIQ) is a key structural component in many biologically active molecules including natural products and synthetic pharmaceuticals. Here, we report on the use of transition-metal mediated [2 + 2 + 2] cyclotrimerisation of alkynes to generate tricyclic THIQs with potential to selectively inhibit AKR1C3.

Evaluation of diagnostic value of AgNOR and PAP in early detection of dysplastic changes in leukoplakia and lichen planus - a preliminary case-control study.

BACKGROUND AND OBJECTIVES: Early detection of oral cancer has been the most effective approach to reduce morbidity and mortality of cancer patients. If a lesion is clinically considered suspicious, an easily practicable, non-invasive, painless, safe, and accurate screening method for detection of the dysplastic changes is necessary. In an attempt to procure this, a study was conducted with the aim of determining the diagnostic accuracy of rapid Papanicolaou stain (PAP) and silver-stained nucleolar organizer regions (AgNOR) in brush biopsies of potentially malignant lesions for early detection of oral cancer. METHODOLOGY: Brush biopsies taken from 25 cases of leukoplakia and lichen planus each were stained with rapid PAP and silver nitrate stains. Histopathological correlation was performed and further compared with rapid PAP and AgNOR for its diagnostic validity. RESULTS: Statistically significant increase in the mean AgNOR count was seen from normal epithelium to lichen planus to that of leukoplakia. When compared with rapid PAP, a linear correlation was seen in AgNOR counts and stages of dysplasia in leukoplakia which was also found to be statistically significant. Diagnostic accuracy for AgNOR in leukoplakia was found to be 84%, lichen planus 73%, whereas RAPID PAP showed 72% accuracy. CONCLUSION: AgNOR analysis may be useful as a quantitative marker of incipient cellular alterations and hence would be helpful in assessing suspicious lesions and thus can be regarded as a valuable adjunct.

Autophagy: A boon or bane in oral cancer.

Autophagy is a catabolic process involving cellular recycling and is believed to play a distinct role in cell survival especially when exposed to stressors, rendering it comparable to the elixir sustaining life. It plays a significant role in various conditions like cancers, neuropathies, heart diseases, auto-immune diseases, etc. Its role in tumorigenesis and cancer therapeutics is worth exploring. Autophagy is believed to help in survival and longevity of cancer cells by buffering metabolic stress. Inhibition of autophagy in an environment of nutrient deprivation leads to cell death. Autophagy is also seen to facilitate metastasizing tumor cells in surviving the conditions of metabolic deprivation and in recovery when conditions turn favorable. Many current cancer therapies tend to inflict metabolic stress, thus autophagy inhibitors may be useful in cancer treatment. As per the adage, "excess of anything is bad", the autophagy promoters can also be exploited as beneficial tools in the fight against cancer. Another method for tumor-cell elimination can be by inducing autophagic cell death through over-stimulation. Oral cancers are becoming a leading cause of deaths worldwide. Much remains to be explored about the role autophagy plays in progression of head and neck cancers, so as to harness it in the therapeutics of these cancers. Research on autophagy is still in its infancy. There are knowledge gaps in understanding this complex process. But there is no doubt that understanding exact mechanism behind autophagy will open up new avenues in cancer therapeutics and even prevention.

Verrucous carcinoma-an enigma: Case report and review.

Verrucous hyperplasia, verrucous keratosis, and VC may not be distinguished clinically or may coexist. Though it appears remarkably harmless, the histopathological diagnosis of VC should be accompanied with careful identification of tumors with a greater chance to become frank cancers. Here, we report two cases of OVC, referring all the diagnostic intricacy occurring in the clinicopathological examination along with a review of the scientific literature.

Oral manifestations of HIV patients in South Indian population.

OBJECTIVES: To study the prevalence of oral manifestations in HIV-infected patients and to correlate oral manifestations with age, gender, severity, and clinical staging. MATERIALS AND METHODS: Fifty patients of either sex diagnosed as HIV positive were included in the study. The data obtained were analyzed statistically using Fisher's exact test and Chi-square test. RESULTS: Among the 50 HIV-infected patients, oral manifestations were found in 40 (80.0%) patients. Thirty (60%) patients were seen in the age range between 31 and 65 years, and 29 (58%) patients were females. Majority of the patients [26 (52%)] were in the clinical staging C, of whom 23 (88.5%) were with manifestations with significant statistical value (P < 0.05). Patients with CD4 count less than 200 had manifestations in 22 (88%) patients. Correlation between reduction in CD4 count and presence of manifestations was significant (P < 0.05). Twenty-eight (80%) patients without antiretroviral therapy (ART) reported with manifestations. Correlation between ART and presence of manifestations was not significant (P = 1.00). INTERPRETATION AND CONCLUSION: Oral manifestations are the indicators for the disease progression. Clinical stage C and lower CD4 count may be useful predictors for HIV, with greater prevalence of oral manifestations.

Ultrasound imaging in the diagnosis of periapical lesions.

BACKGROUND AND OBJECTIVES: To assess the diagnostic capability of real-time ultrasound imaging, together with the application of color power Doppler in the identification and differential diagnosis of the periapical lesions. MATERIALS AND METHODS: Fifteen patients with periapical lesions of pulpal origin, diagnosed with clinical and conventional radiographic examination, were examined further using ultrasonography. The results from the biopsies of the lesions were compared and statistically analyzed. RESULTS: The differential diagnosis between periapical granulomas and cystic lesions, which were based on the ultrasonographic findings, were confirmed by the results of the histopathologic examination in 13 (86.7%) of 15 cases, one being granuloma and 14 being cystic lesion. INTERPRETATION AND CONCLUSION: Ultrasound real-time imaging is a technique that may help make a differential diagnosis between cysts and granulomas by revealing the nature of the content of a bony lesion. This technique may have further applications in the study of other lesions of the jaws.

Chemical studies on polyaniline titanotungstate and its uses to reduction cesium from solutions and polluted milk.

Polyaniline titanotungstate (PATiW) was synthesized by the sol-gel method. Adsorption isotherm studies of Cs(+) from aqueous solution are described. Elemental Composition, chemical solubility, ion-exchange capacity (IEC) and pH-titration curve are studied. Distribution coefficients (K(d)) for 10 metal ions were determined. It was found that the polyaniline titanotungstate is highly selective to Cs(+) and the selectivity order is Cs(+)>>>Zr(4+)>Mo(6+)>V(5+)>As(5+)>Cr(3+)>Co(2+)>Cu(2+)>Zn(2+)>Cd(2+). The adsorbent capacity was determined using the Freundlich and Langmuir adsorption isotherm models. The Cs(+) adsorption isotherm data fit best to the Freundlich isotherm model. The maximum Cs(+) uptake of polyaniline titanotungstate was found to be 217 mg g(-1). Column tests were performed to determine the breakthrough curves with varying bed depths and flow rates in different solutions. The results showed that the half breakthrough time increases proportionally with increasing bed depths. Kinetic studies for removal of cesium from milk were also investigated using a scintillation detector head (NaI).

Oral manifestations and radiographic changes in the jaw-bones of patients with end-stage renal disease onmaintenance hemodialysis: a descriptive study / Estudo descritivo das manifestações bucais e alterações radiográficas em maxilares de pacientes com doençarenal terminal e sob hemodiálise

Objectives: The purpose of the present study was to assess the oral manifestations and radiographic changes in the jawbones of patients undergoing hemodialysis, diagnosed with end-stage renal disease (ESRD). Methods: Forty patients on maintenance hemodialysis were clinically examined for oral manifestations and evaluated for radiographic changes in the jaws with panoramic and intra-oral periapical radiographs. Results were expressed as Percentage. Results: Out of 40 patients, 37 patients (92.5%) showed at least one or more oral manifestations. The most common oral manifestations were mucosal pallor (70%), xerostomia (57.5%), petechiae and ecchymoses (37.5%), and less common were taste alterations (15%), uremic odor (7.5%), coated tongue (10%) and mucosal pain (2.5%). Radiographic changes seen were loss of lamina dura (22.2%), altered trabecular pattern (5.5%), multiple radiolucent lesions (5%), and pulp calcification (2.7%). Conclusions: Most of the patients presented with oral signs and symptoms. However it was observed that patients demonstrating radiographic changes were mostly those who were on dialysis for a relatively long duration.

Objetivos: O objetivo do presente estudo foi avaliar as manifestações orais e alterações radiográficas nos maxilares de pacientes submetidos à hemodiálise e com diagnóstico de doença renal em estágio terminal (DRET). Métodos: 40 pacientes em hemodiálise de manutenção foram examinados clinicamente e avaliados radiograficamente por meio de radiografias panorâmicas e periapicais em busca de manifestações orais nas mandíbulas. Resultados: Dos 40 pacientes, 37 pacientes (92,5%) apresentaram pelo menos uma ou mais manifestações orais. As manifestações orais mais comuns foram: palidez da mucosa (70%), xerostomia (57,5%), petéquias e equimoses (37,5%); e menos comuns: alterações do paladar (15%), odor urêmico (7,5%), língua saburrosa (10%) e mucosa dolorida (2,5%). As alterações radiográficas observadas foram a perda da lâmina dura (22,2%), padrão trabecular alterado (5,5%), lesões radiolúcidas múltiplas (5%) e calcificação pulpar (2,7%). Conclusões: A maioria dos pacientes apresentava sinais e sintomas orais. Entretanto, foi observado que os pacientes demonstrando alterações radiográficas foram principalmente aqueles que estavam em diálise por um período relativamente longo.

Prophylactic role of curcumin in dextran sulfate sodium (DSS)-induced ulcerative colitis murine model.

We have addressed in this study the possible protective role of the main principle of turmeric pigment; curcumin on a murine model of ulcerative colitis (UC). Colitis was induced by administration of dextran sulfate sodium (DSS) (3% W/V) in drinking water to male Swiss albino rats for 5 consecutive days. DSS challenge induced UC model that was well characterized morphologically and biochemically. DSS produced shrinkage of colon length and increased the relative colon weight/length ratio accompanied by mucosal edema and bloody stool. Histologically, DSS produced submucosal erosions, ulceration, inflammatory cell infiltration and crypt abscess as well as epithelioglandular hyperplasia. The model was confirmed biochemically, and the test battery entailed elevated serum tumor necrosis factor (TNF-alpha) and colonic activity of myleoperoxidase (MPO). Colonic glutathione-S-transferase (GST) activity and its substrate concentration; GSH, were notably reduced, while lipid peroxidation, expressed as malondialdehyde (MDA) level, and total nitric oxide (NO) were significantly increased. Prior administration of curcumin (100mg/kg, IP) for 7 consecutive days ahead of DSS challenge mitigated the injurious effects of DSS and ameliorated all the altered biochemical parameters. These results suggest that curcumin could possibly have a protective role in ulcerative colitis probably via regulation of oxidant/anti-oxidant balance and modulation of the release of some inflammatory endocoids, namely TNF-alpha and NO.

Desmoplastic ameloblastoma in the maxilla: a case report and review of literature.

Desmoplastic ameloblastoma (DA) is a rare variant of ameloblastoma (AM). The location of this lesion, its histology and radiological features differ from those of conventional AM. We report a case of DA in the canine / premolar region of the left maxilla of a 32-year-old woman and present a brief review of the literature. Radiographically, it had a mixed radiolucent / radiopaque appearance with ill-defined margins. Histologically, the tumor was characterized by extensive stromal desmoplasia and small tumor islands of odontogenic epithelium in the stroma, along with a few areas of reactive bone formation. The tumor was treated by partial maxillectomy and the patient was disease free after 1 year.

Mandibular antegonial and ramus notch depths and condylar bone change.

The present study sought to clarify the relationship between antegonial and ramus notch depths and condylar bone change, and analyse the effects of such change on craniofacial structure. The study sample was of 28 pre-orthodontic patients with signs and symptoms of temporomandibular joint (TMJ) disorders, who underwent helical computed tomography to diagnose their TMJ pathology. Craniofacial structures were compared between 14 subjects with bilateral condylar bone change (BBC group: two male and 12 female) and 14 subjects with no bone change (NBC group: two male and 12 female). Sella-nasion-point B (SNB) and point A-nasion-point B (ANB) angles were significantly smaller in BBC than in NBC, with ramus height and mandibular body lengths significantly shorter in BBC than in NBC. The BBC lower facial height and SN-Go-Ar angle, as well as antegonial and ramus notch depths, were significantly greater than in NBC, and the mandible was significantly more retruded in BBC than in NBC. These results showed that condylar bone change might be related not only to mandibular size (e.g. retrusion) but also to mandibular outline (including antegonial and ramus notch depth).