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Bacterial infections and persistent inflammation can impede the intrinsic healing process of wounds. To combat this issue, researchers have delved into the potential use of carbon dots (CDs) in the regulation of inflammation and counteract infections. These CDs were synthesized using a microwave-assisted hydrothermal process and have demonstrated outstanding antibacterial and antibiofilm properties against Gram-positive and Gram-negative bacteria. Additionally, CDs displayed biocompatibility at therapeutic concentrations and the ability to specifically target mitochondria. CD treatment effectively nullified lipopolysaccharide-triggered reactive oxygen species production by macrophages, while simultaneously promoting macrophage polarization toward an anti-inflammatory phenotype (M2), leading to a reduction in inflammation and an acceleration in wound healing. In vitro scratch assays also revealed that CDs facilitated the tissue-repairing process by stimulating epithelial cell migration during reepithelialization. In vivo studies using CDs topically applied to lipopolysaccharide (LPS)-stimulated wounds in C57/BL6 mice demonstrated significant improvements in wound healing due to enhanced fibroblast proliferation, angiogenesis, and collagen deposition. Crucially, histological investigations showed no indications of systemic toxicity in vital organs. Collectively, the application of CDs has shown immense potential in speeding up the wound-healing process by regulating inflammation, preventing bacterial infections, and promoting tissue repair. These results suggest that further clinical translation of CDs should be considered.

Garcinol (GAR) is a polyisoprenylated benzophenone obtained from Garcinia indica used as anti-oxidant and anti-inflammatory in traditional medicine and due to these activities, it possesses anticancer properties. It is considered to be a next generation epigenetic drug. A green solvent based analytical method which is efficient, sophisticated, and highly enriched has been developed for the quantitative analysis of GAR in biological samples (plasma, liver, kidney and spleen) with the use of deep eutectic solvent (DES) for its extraction. A series of 23 DESs were synthesized and out of which, Thymol (Th)-Terpeniol (T), 2:1 molar ratio with a more hydrophobic environment and high interaction efficiency between GAR and DES was identified for the better extraction from mice plasma and tissue samples. The Design of Experiment approaches like placket-burmann design and central composite design were used to optimize the method conditions. The method validation characteristics, such as limit of detection (0.193-0.237 ng/mL), limit of quantification (0.644-0.697 ng/mL), lower limit of quantification (0.5 ng/mL), broad range of linearity with R 2 (0.9994-0.9997) with a percent recovery not less than 87% was observed, which are well within the acceptance criteria for a bioanalytical method. The enrichment factor is upto 53-60 folds, with high extraction efficiency (89-97%). The measurement uncertainty was estimated with an expanded uncertainty ranged between 10.9%-19.0%. The method developed and validated was effectively applied to examine the pharmacokinetic and biodistribution patterns for GAR in mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Indolemethane derivatives are significant molecules in the study of N -heterocyclic chemistry. Herein, we designed and developed a highly efficient green synthesis of indolemethane compounds using a recyclable biodegradable glycerol-based carbon solid acid catalyst under solvent-free conditions at room temperature for 5 min with excellent yields. The synthesized compounds were subjected to cytotoxic activity against prostate (DU145), hepatocellular carcinoma (HepG2), and melanoma (B16) cell lines. The highest cytotoxicity effects were found with 1k (1.09 μM) and 1c (2.02 μM) against DU145, followed by 1a , 1d , 1f , 1n , and 1m between 5.10 and 8.18 μM concentrations. The anticancer activity is validated using molecular docking simulations, and comparing binding energies with the standard drug doxorubicin suggests that the title compounds are well fitted into the active site pocket of the target molecules.., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Phthalate compounds were found to disrupt the endocrine system and alter transcriptomes during human embryonic development. In our previous work, we have isolated and reported two such phthalates di-(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) from Brevibacterium mcbrellneri bacteria and evaluated their bioactive properties. Naturally derived phthalates might be less toxic compared with synthesized molecules. We have investigated biologically isolated phthalates to understand the possible genotoxic effects in mice and further investigated in silico binding and polymerization of β-tubulin. Three sub-lethal concentrations of DEHP (150 μM, 175 μM, and 200 μM) and DBP (10 μM, 15 μM, and 30 μM) were studied. The results showed that the phthalates were found to be highly genotoxic in nature. However, the pattern of genotoxic effects was not found to be dose-dependent in the induction of chromosome aberrations (CA), micronuclei (MN), and changes in the mitotic index (MI) in cells. In silico studies of phthalates on polymerization of β-tubulin suggested that both DBP and DEHP were able to interact with the hydrogen bonds and make strong van der Waals interactions with β-tubulin thereby possibly causing destabilization of microtubule network. Our study suggests that these phthalates might be playing an important role in normal cell division thereby showing highly genotoxic effects.

Green nanotechnology has recently attracted a lot of attention as a potential technique for drug development. In the present study, silver nanoparticles were synthesised by using Sargassum tenerrimum, a marine seaweed crude extract (Ag-ST), and evaluated for antimalarial activity in both in vitro and in vivo models. The results showed that Ag-ST nanoparticles exhibited good antiplasmodial activity with IC 50 values 7.71±0.39 µg/ml and 23.93±2.27 µg/ml against P. falciparum and P. berghei respectively. These nanoparticles also showed less haemolysis activity suggesting their possible use in therapeutics. Further, P. berghei infected C57BL/6 mice were used for the four-day suppressive, curative and prophylactic assays where it was noticed that the Ag-ST nanoparticles significantly reduced the parasitaemia and there were no toxic effects observed in the biochemical and haematological parameters. Further to understand its possible toxic effects, both in vitro and in vivo genotoxicological studies were performed which revealed that these nanoparticles are non-genotoxic in nature. The possible antimalarial activity of Ag-ST may be due to the presence of bioactive phytochemicals and silver ions. Moreover, the phytochemicals prevent the nonspecific release of ions responsible for low genotoxicity. Together, the bio-efficacy and toxicology outcomes demonstrated that the green synthesized silver nanoparticles (Ag-ST) could be a cutting-edge alternative for therapeutic applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Our earlier reports established that zinc oxide nanoflowers (ZONF) show significant pro-angiogenic properties, where reactive oxygen species, nitric oxide and MAPK-AKT-eNOS cell signaling axis play an essential task. Considering the significance of angiogenesis in healthcare, our research group has recently demonstrated the in vivo therapeutic application of ZONF (10 mg/kg b.w.) for treating peripheral artery disease. Moreover, based on the angio-neural crosstalk between vascular and neuronal systems, we have further demonstrated the neuritogenic and neuroprotective characteristics of pro-angiogenic nanoflowers (10 mg/kg b.w.) for the treatment of cerebral ischemia. However, it is crucial for a therapeutic material to be non-toxic for its practical clinical applications and therefore assessment of its in vivo toxicity and adverse effect is highly important. Herein, for the first time, we investigate a detailed nanotoxicology of therapeutically active ZONF in Swiss albino mice to evaluate their safety profile and comprehend their aspects for future clinical applications. The maximum tolerated dose (MTD) of ZONF was found to be 512.5 mg/kg b.w. which was employed for acute exposure (2 weeks), showing slight toxicity. However, sub-chronic (4 weeks) and long term chronic (8-12 weeks) studies of nanoflowers exhibited their non-toxic nature particularly at lower therapeutic doses (1-10 mg/kg b.w.). Additionally, in depth genotoxicity study revealed that lower therapeutic dose of ZONF (10 mg/kg b.w.) did not exhibit significant toxicity even in genetic level. Overall, the present nanotoxicology of ZONF suggests their high biocompatible nature at therapeutic dose, offering the basis of their future clinical applications in ischemic and other vascular diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Lichen secondary metabolites are well explored medicinal agents with diverse pharmacological properties. One of the important antibiotic lichen secondary metabolites is usnic acid. Its diverse medicinal profiles prompted us to explore it as a potential antitubercular molecule. Towards this direction, continuing our efforts on the discovery and development of new analogs with potent antitubercular properties we designed, synthesized, and evaluated a set of 37 usnic acid enaminone-coupled aryl-n-hexanamides (3-39). The study yielded a 3,4-dimethoxyphenyl compound (13, 5.3 µM) as the most active anti-TB molecule. The docking studies were performed on 7 different enzymes to better understand the binding modes, where it was observed that compound 13 bound strongly with glucose dehydrogenase (Gscore: - 9.03). Further antibacterial investigations revealed compound 2 with potent inhibition on Salmonella typhi and Bacillus subtilis (MIC 3 µM) and MIC values of 7 and 14 µM on Streptococcus mutans and Escherichia coli respectively. Compound 19 (3-F-5-CF 3 -phenyl) displayed encouraging antibacterial profiles against E. coli, S. typhi and S. mutans with MIC values of 10 µM respectively. Interestingly, compound 20 (2,6-difluorophenyl) also displayed good antibacterial activity against E. coli with an MIC value of 6 µM. These encouraging pharmacological results will help for better designing and developing usnic acid-based semi-synthetic derivatives as potential antimicrobial agents. A set of 37 new usnic acid enaminone-coupled aryl-n-hexanamides were synthesized and evaluated as potential antimicrobial agents. Compound 13 was identified as the most active antitubercular molecule. 13 was further docked against 7 different enzymes of tuberculosis. The molecule displayed maximum binding energy with the enzyme Glucose dehydrogenase (Gscore: - 9.03), indicating that these hexanamides possibly act by inhibiting the glucose metabolic pathway of the bacterium. Surprisingly, the intermediate hexanoic acid 2 was identified as potent antibacterial agent, acting on both gram-positive and gram-negative bacterial strains (3-14 μM). The active compounds may be subjected to structural iterations to develop further leads., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Novel almazole D-amide conjugates, esters, and N-alkylated analogs were synthesized and investigated for their anticancer activity against seven cancer cell lines. Among the series, compounds 5g and 5m showed significant anticancer activities against multiple cell lines with moderate selectivity indices. Compound 5g had IC 50 values of 5.86 ± 0.31, 9.94 ± 0.06, 12.74 ± 0.12, and 9.40 ± 0.03 μM against the B16-F10, DU145, HeLa, and LC-540 cell lines, respectively, while compound 5m showed IC 50 values of 6.35 ± 0.09, 9.17 ± 0.11, 9.00 ± 0.011, 19.65 ± 0.63, 8.13 ± 0.04, and 11.56 ± 0.01 μM against B16-F10, DU145, HeLa, HepG2, LC-540, and SK-BR-3 cells, respectively. Compared to almazole D, which only showed significant activity against B16-F10 cells (IC 50  = 9.05 ± 0.008 μM), the synthesized analogs showed improved anticancer activity against multiple cell lines. The kinase inhibition assay coupled with the docking studies revealed that epidermal growth factor receptor (EGFR) kinase inhibition via interaction with amino acid residue T790 on the EGFR is one of the possible mechanisms by which 5g exerts its anticancer potential. The ADMET prediction and drug-likeness of the analogs project the synthesized analogs as promising agents, which can be further developed for application in cancer therapy., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

A novel I 2 /TBHP mediated domino synthesis of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2 H )-yl)- N -phenyl benzamides by reaction of isatins with o -amino N -aryl/alkyl benzamides was described. This was the first application of o -amino N -aryl/alkyl benzamides participating in oxidative rearrangement with isatins for synthesis of desired products. The synthesized compounds contained amide and quinazoline units and their combination resulted in molecular hybridization of two important pharmacophores. In this study, the synthesized compounds 3a-r were screened for cytotoxicity against four cancer cell lines A549, DU145, B16-F10, and HepG2 and also non-cancerous cell line CHO-K1. The compounds 3c, 3l and 3o gave promising results. The in silico molecular docking studies (PDB ID 1N37) also validated the anticancer activity of these compounds showing good binding affinity with target DNA and by acting as DNA intercalators., Competing Interests: The authors declare that they have no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Nanotechnology has immensely advanced the field of cancer diagnostics and treatment by introducing potential delivery vehicles as carriers for drugs or therapeutic agents. In due course, mesoporous silica nanoparticles (MSNs) have emerged as excellent vehicles for delivering drugs, biomolecules, and biomaterials, attributed to their solid framework and porosity providing a higher surface area for decorating with various functional ligands. Recently, the metal tin (Sn) has gained huge importance in cancer research owing to its excellent cytotoxicity and ability to kill cancer cells. In the present work, we synthesized MSNs, conjugated them with organotin compounds, and characterized them using various physicochemical techniques. Subsequently, the biological evaluation of MSN (S1), MSN-MP (S2) and tin-conjugated MSNs (S3: MSN-MP-SnPh 3 ) (MP = 3-mercaptopropyltriethoxysilane) revealed that these nanoconjugates induced cytotoxicity, necrosis, and apoptosis in MCF-7 cells. Moreover, these nanoconjugates exhibited anti-angiogenic properties as demonstrated in the chick embryo model. The increase of reactive oxygen species (ROS) was found as a one of the plausible mechanisms underlying cancer cell cytotoxicity induced by these nanoconjugates, encouraging their application for the treatment of cancer. The tin-conjugated MSNs demonstrated less toxicity to normal cells compared to cancer cells. Furthermore, the genotoxicity studies revealed the clastogenic and aneugenic effects of these nanoconjugates in CHO cells mostly at high concentrations. These interesting observations are behind the idea of developing tin-conjugated MSNs as prospective candidates for anticancer therapy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Silver nanoparticles were green synthesized (Ag-PTs) employing the crude extract of Padina tetrastromatica , a marine alga, and their anticancer and safety profile were compared with those of chemically synthesized silver nanoparticles (Ag-NPs) by in vitro and in vivo models. Ag-PT exhibited potent cytotoxicity against B16-F10 (IC 50 = 3.29), MCF-7 (IC 50 = 4.36), HEPG2 (IC 50 =3.89), and HeLa (IC 50 = 4.97) cancer cell lines, whereas they exhibited lower toxicity on normal CHO-K1 cells (IC 50 = 5.16). The potent anticancer activity of Ag-PTs on cancer cells is due to the liberation of ions from the nanoparticles. Increased ion internalization to the cells promotes reactive oxygen species (ROS) production and ultimately leads to cell death. The in vitro anticancer results and in vivo melanoma tumor regression study showed significant inhibition of melanoma tumor growth due to Ag-PT treatment. Ag-PT is involved in the upregulation of the p53 protein and downregulation of Sox-2 along with the Ki-67 protein. The antitumor effects of Ag-PTs may be due to the additional release of ions at a lower pH of the tumor microenvironment than that of the normal tissue. The results of safety investigations of Ag-PT by studying mitotic chromosome aberrations (CAs), micronucleus (MN) induction, and mitotic index (MI) demonstrated Ag-PT to be less genotoxic compared to Ag-NP. The bioefficacy and toxicology outcomes together demonstrated that the green synthesized silver nanoparticles (Ag-PTs) could be explored to develop a biocompatible, therapeutic agent and a vehicle of drug delivery for various biomedical applications.

Ag 3 PO 4 nanostructures (APNs) containing silver (Ag metal; of the noble metal families) have the potential to exhibit enzyme-mimetic activity. A nanostructure shape, including its surface facets, can improve the bioactivity of enzyme mimicry, yet the molecular mechanisms remain unclear. Herein, we report facet-dependent peroxidase and oxidase-like activity of APNs with both antibacterial and biofilm degrading properties through the generation of reactive oxygen species. Cubic APNs had superior antibacterial effects than rhombic dodecahedral shapes when inhibiting Gram-positive and Gram-negative bacterial pathogen proliferation and biofilm degradation. A similar performance was observed for rhombic dodecahedral shapes, being greater than tetrahedral-shaped APNs. The extent of enzyme-mimetic activity is attributed to the facets {100} present in cubic APNs that led the peroxide radicals to inhibit the proliferation of bacteria and degrade biofilm. These facets were compared to rhombic dodecahedral APNs {110} and tetrahedral APNs {111}, respectively, to reveal a facet-dependent enhanced antibacterial activity, providing a plausible mechanism for shape-dependent APNs material enzyme-mimetic effects on bacteria. Thus, our research findings can provide a direction to optimize bactericidal materials using APNs in clinically relevant applications., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

OBJECTIVE. The purpose of this study was to investigate the reproducibility of three quantitative MRI parameters associated with patellar instability and to determine whether they measure anatomic predisposition to patellar instability individually or in combination with the other parameters. MATERIALS AND METHODS. In this retrospective study, 100 patients diagnosed with a patellar dislocation injury and 100 age- and sex-matched control patients were examined using MRI. The distance between the tibial tubercle and posterior cruciate ligament (TT-PCL), distance between the tibial tubercle and trochlear groove (TT-TG), and TG depth (trochlear dysplasia) were measured independently by three fellowship-trained musculoskeletal radiologists. Intraclass correlation coefficient (ICC) was used to assess intraobserver and interobserver reliability. The parameters in both groups were tested for interdependence on each other and were compared for prevalence and association with patellar instability. RESULTS. All three parameters showed almost perfect intraobserver (TT-PCL ICC, ≥ 0.88; TT-TG ICC, 0.96; trochlear dysplasia ICC, ≥ 0.92) and interobserver (TT-PCL ICC, 0.82; TT-TG ICC, 0.94; trochlear dysplasia ICC, 0.91) reliability and were significantly more common in the patellar instability group. Trochlear dysplasia had the highest association with patellar instability, both as a unique parameter and in pairwise combination with an abnormal TT-TG. Optimal cutoff thresholds for normal TT-TG and TT-PCL were 15.00 mm or less and 21.30 mm or less, respectively. The optimal normal cutoff threshold for evaluating trochlear dysplasia via trochlear depth was 4.95 mm or more. CONCLUSION. Patellar instability is multifactorial. Highly reproducible parameters derived from MRI reveal both unique and overlapping anatomic predispositions, and considering all parameters together may help individualize patient management when selecting orthopedic procedures.

The dormant and resistant form of Mycobacterium tuberculosis presents a challenge in developing new anti-tubercular drugs. Herein, we report the synthesis and evaluation of trisubstituted thiazoles as antituberculosis agents. The SAR study has identified a requirement of hydrophobic substituent at C2, ester functionality at C4, and various groups with hydrogen bond acceptor character at C5 of thiazole scaffold. This has led to the identification of 13h and 13p as lead compounds. These compounds inhibited the dormant Mycobacterium tuberculosis H37Ra strain and M. tuberculosis H37Rv selectively. Importantly, 13h and 13p were non-toxic to CHO cells. The 13p showed activity against multidrug-resistant tuberculosis isolates., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The first synthesis of a phenolic natural monoacylglycerol (1- [11-(ferulyloxy) undecanoyl)] glycerol) was carried out by bioorganic synthesis starting from ferulic acid. The synthetic route of the target lipidic compound was designed involving a chemo-enzymatic approach using immobilized Candida antarctica lipase as biocatalyst in two of the steps conducted in organic medium. The prepared lipidic compound was characterized by using spectral data and evaluated for antimicrobial, antioxidant and cytotoxic studies to examine its potential. The synthesized compound showed moderate antimicrobial activity and showed very good antioxidant activity in DPPH radical scavenging assay and also in oxidation inhibition in soybean oil by differential scanning calorimetry. The cytotoxic studies of the synthetic lipid showed promising activity against A549 and HeLa cancer cell lines with IC 50 values of 9.102 and 9.886 μM respectively. The prepared compound can be useful in designing novel phenolic lipids with potential applications in cosmetic and biomedical fields., Competing Interests: We declare that we have no conflict of interests., (© 2019 The Authors. Published by Elsevier B.V.)

The development of an effective antitubercular agent is a challenge due to the complex nature of tuberculosis. Herein, we report the synthesis and evaluation of α-aminoacyl amides as antitubercular agents. The systematic medicinal chemistry approach led to identification of optimal substitutions required for the activity. Compound 11l was identified as antitubercular lead with drug like properties. Further, 11l selectively inhibited M. tuberculosis H37Rv with MIC value of 0.78 μM and was found to be non-toxic to CHOK1 cells. The lead compound inhibited multidrug resistant and Pre-Extensively drug resistant strains of Mycobacterium at 2 μg/mL and 8 μg/mL respectively., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Calcium carbonate (CaCO 3 )-based materials as feasible pH-sensitive drug carriers, which can actively dissolve in an acidic microenvironment of cancer cells, are finding increasing importance. This has drawn our interest in the development of a bioinspired polypeptide- mediated method to design calcium carbonate microspheres loaded with tetracycline (CaCO 3 -TC) with an aim to explore its safe application in cancer therapeutics. Its therapeutic application in cancer patients essentially demands its safety information on the normal cells. Herein our study presents the in vitro genetic toxicological information on CaCO 3 -TC using noncancerous mammalian CHO cells in comparison to bare TC at three different concentrations (100, 200, and 300 μM) selected based on the cytotoxicity data (MTT). Assessment of various end points like chromosome aberrations, micronucleus, mitotic index and effects on cell cycle distribution after 24 h post-treatment demonstrates a significant reduction in clastogenic ( P < 0.001), aneugenic potential ( P < 0.05), and nonmitotoxic nature of CaCO 3 -TC than that of bare TC. Noticeably, as inferred from the FACS analysis on cancer cells, G 2 /M phase accumulation in breast cancer cells (MDA-MB-231), and at G 1 phase in cervical cancer cells (HeLa) reveal its potential anticancer property. On the other hand, the genotoxicity studies illustrate protective effects of CaCO 3 -TC on noncancerous cells. While the pH-dependent dissolution property of the CaCO 3 matrix encasing tetracycline results in higher toxicity on cancer cells, the near neutral pH in the case of normal cells prevents complete dissolution of CaCO 3 thereby not allowing the encapsulated TC to adequately interact with the cells. Therefore, thus assembled CaCO 3 spheres not only provide a way for facile encapsulation of tetracycline under mild conditions but also result in an effective matrix for differential toxicity toward normal and cancer cells justifying its clinical development as a novel target-specific drug in therapeutic applications for metastatic cancers.

Aims: Zoledronic acid (ZA), a FDA approved drug has used widely in the treatment of bone metastasis complications, has been linked to renal toxicity with unclear mechanism. The present study is aimed at investigating the genotoxic and cytotoxic effects of ZA in renal epithelial cells., Main Methods: The genotoxic effect of ZA in Vero and MDCK cells determined by cytokinesis block micronucleus (CBMN) assay. The cytotoxic effect assessed by analysing cell cycle profile, cell death and mitochondrial membrane potential by flow cytometry using propidium iodide, AnnexinV-FITC/PI and JC1 dye staining, respectively, BAX and Bcl-2 expression by Western blotting and caspase activity by spectrofluorimetry., Key Findings: The cytotoxic effect of ZA based on MTT assay revealed variable sensitivities of Vero and MDCK cells, with IC 50 values of 7.41 and 109.58 μM, respectively. The CBMN assay has shown prominent dose-dependent (IC 10-50 ) induction of micronuclei formation in both cells, indicating ZA's clastogenic and aneugenic potential. Further, the ZA treatment led the cells to apoptosis, evident from dose-dependent increase in the percentage of cells in subG1 phase and display of membranous phosphatidylserine translocation. Studies also confirmed apoptosis through mitochondria, evident from the prominent increase in BAX/Bcl-2 ratio, mitochondrial membrane depolarization and caspase-3/7 activity. In addition, ZA reduces cytokinetic activity of renal cells, evident from dose-wise lowered replicative indices., Significance: The study depict ZA's potential genotoxic effect along with cytotoxic effect in renal epithelial cells, could be key factors for the development of renal complications associated with it, which prompts renal safety measures in lieu with ZA usage., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Costunolide (CE) is a sesquiterpene lactone well-known for its antihepatotoxic, antiulcer, and anticancer activities. The present study focused on the evaluation of the cytogenetic toxicity and cellular death-inducing potential of CE in CHO cells, an epithelial cell line derived from normal ovary cells of Chinese hamster. The cytotoxic effect denoting MTT assay has shown an IC 50 value of 7.56 μM CE, where 50% proliferation inhibition occurs. The oxidative stress caused by CE was confirmed based on GSH depletion induced cell death, conspicuously absent in N-acetylcysteine (GSH precursor) pretreated cells. The evaluation of genotoxic effects of CE using cytokinesis block micronucleus assay and chromosomal aberration test has shown prominent induction of binucleated micronucleated cells and aberrant metaphases bearing chromatid and chromosomal breaks, indicating CE's clastogenic and aneugenic potential. The apoptotic death in CE treated cells was confirmed by an increase in the number of cells in subG1 phase, exhibiting chromatin condensation and membranous phosphatidylserine translocation. The apoptosis induction follows mitochondrial mediation, evident from an increase in the BAX/Bcl-2 ratio, caspase-3/7 activity, and mitochondrial membrane permeability. CE also induces cytostasis in addition to apoptosis, substantiated by the reduced cytokinetic (replicative indices) and mitotic (mitotic indices and histone H3 Ser-10 phosphorylation) activities. Overall, the cellular GSH depletion and potential genotoxic effects by CE led the CHO cells to commit apoptosis and lowered cell division. The observed sensitivity of CHO cells doubts unintended adverse effects of CE on normal healthy cells, suggesting higher essentiality of further studies in order to establish its safety efficacy in therapeutic explorations.

Dehydrocostus lactone (DHCL), a sesquiterpene lactone is well-known for its antiulcer, anti-hepatotoxic and anticancer activity. However, the studies concerning the safety/toxicity potential of DHCL toward the cells of normal origin remain unclear. The present study is aimed at investigating the toxicity potential of DHCL in renal distal tubular and interstitial fibroblast cell lines (MDCK and NRK-49F cells, respectively), and also in ovarian epithelial cell line (CHO cells). The MTT assay has predicted potential cytotoxic activity of DHCL against the cell line types with IC 50 values of 0.99, 2.1 and 5.15??M, respectively. The prominent dose-dependent (IC 30,50 & 70 ) increase in the percentage of cells at subG1 phase in all the cell lines revealed apoptosis induction, further establishing the cytotoxic effect of DHCL. The DHCL exposure (4?h) revealed the induction of ROS in both renal cell lines, which is responsible for apoptosis induction. The NRK-49F cells displayed dose-wise (IC 30-70 ) increase in chromatin condensation and membranous phosphatidylserine translocation further confirming apoptotic cell death. Also, their increase in BAX/Bcl-2 ratio, mitochondrial membrane permeability and caspase-3/7 activity establishes mitochondrial mediated apoptosis. In case of CHO cells, the higher percentage of cells at G2/M phase and expression of Cyclin B1 at lower concentration of DHCL (?IC 30 ), indicate mitotic arrest. The incidence of chromatid gaps and negligible micronuclei formation in treated cells (IC 10-30 ) suggest that sub-lethal concentrations of DHCL exposure causes mitotic arrest in response to the damages by steady expression of Cyclin B1. Under in vitro condition, the study of DHCL's potential cytotoxic effect on both kidney cells and ovarian epithelial cells indicated the possibility of adverse effects on normal healthy cells as well. Hence, the study recommends in-depth investigations on DHCL usage concerning its safety in therapeutic applications., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objectives: The aims of this study were to assess computed tomography enhancement of pancreatic neuroendocrine tumors (NETs), determine correlation with histological vascularity and fibrosis, and identify a biomarker for tumor aggression., Methods: The arterial and venous enhancement of NET was calculated on computed tomography for 56 patients. Tumor size and vascularity/fibrosis were assessed. Tumor aggression was grouped by World Health Organization and Hochwald grade and the presence of metastases. Variables were assessed for correlation. Groups were compared using t test/Wilcoxon rank sum test., Results: Arterial enhancement and dynamic washout (r = 0.35, P = 0.02; r = 0.34, P = 0.02, respectively) correlate with vascularity. There is inverse correlation between vascularity and fibrosis (r = -0.62, P < 0.001), but no correlation between enhancement and fibrosis. Metastatic NET had less arterial (mean, -2 [standard deviationi {SD}, 27.1] Hounsfield unit [HU]; 35.7 [SD, 57.5] HU; P = 0.01) and venous (12.6 [SD, 14.4] HU; 29.2 [SD, 38.3] HU; P = 0.04) enhancement and less washout (8.5 [SD, 18.5] HU; 26.8 [SD, 30] HU, P = 0.02) compared with nonmetastatic NET. These differences were not present when comparing by tumor grade. Arterial hypoenhancement was the only significant predictor of metastases., Conclusions: Aggressive tumors, as determined by metastases, but not histological grade, enhance less than nonmetastatic tumors.

Background/objectives: There are inconsistencies in the literature regarding the clinical significance of cystic components in pancreatic neuroendocrine tumors (NET). This may be related to differences in the identification of cystic NET through imaging and/or pathology. Tumors may also be microscopically or macroscopically cystic. Our primary objective is to determine radiology-pathology correlation for the identification of cystic components. Our secondary objective is to determine if cystic components are associated with indices of tumor aggression., Methods: 60 tumors with correlative surgical pathology were assessed retrospectively for cystic components on CT and pathology. Tumor was categorized as solid or cystic on CT and pathology. If cystic on pathology, cystic components were categorized as macroscopic or microscopic. Cystic components were estimated as <50% and ≥50% tumor volume. WHO/Hochwald grade and presence of metastases were used to stratify disease aggression. Associations were tested with Chi square/Fisher's exact test and differences were tested with t-test/Wilcoxon rank sums test., Results: There is moderate agreement between CT and histology for presence of cystic components. Discrepancies were mostly attributable to the presence of microscopic cystic components in tumors appearing solid on CT. There was no difference in size between cystic and solid tumors on CT or pathology. No association between CT-determined cystic components and tumor grade was found. Tumors with cystic components (cystic by CT, and macroscopically cystic by pathology) demonstrated less association with metastases than solid tumors., Conclusions: Cystic components, comprising ≥50% of the tumor by CT and observed macroscopically on pathology, are associated with less aggressive disease., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)