HeLa Research Articles

Harnessing bright upconversion luminescence from PEG-coated NaGdF4:Ho3+/Yb3+ nanoparticles for contrast enhancement in dual mode OCT imaging and optical temperature sensing

In this work, authors synthesized the Polyethylene Glycol (PEG) coated NaGdF4:Ho3+/Yb3+ nanoparticles using the thermal decomposition reaction route. Our primary objective was to comprehensively evaluate their suitability for augmenting image contrast, particularly within the intricate domain of Swept Source Optical Coherence Tomography (SSOCT) and photo-thermal Optical Coherence Tomography (PTOCT) imaging modalities. Our meticulous inquiry yielded the revelation of extraordinary upconversion emissions, which emanated from the distinct transitions of Ho3+ ions, most notably the 5F4(5S2)→ 5I8 and 5F5→ 5I8 transitions. These transitions manifested as strikingly vibrant green emissions, precisely at the 539 nm and 661 nm wavelengths. Furthermore, we investigated the underlying upconversion mechanism, delving deeply into the elucidation of decay times and the nanoparticles' ability to transform incident radiation into thermal energy. Impressively, these nanoparticles exhibited a noteworthy photo-thermal conversion efficiency, specifically measured at an impressive 47.4% along with the bright green luminescence. Our study also extended to bio-compatibility, where we achieved highly encouraging outcomes. Following 24 hours of incubation with HeLa cells treated with UCNP-PEG, we ascertained a compelling cell survival rate exceeding 80%, underscoring the favorable biocompatibility of these nanoparticles. Moreover, these nanoparticles demonstrated a conspicuous thermal sensitivity, quantified at 5.1×10-3 K-1 at 380K, thus signaling their potential for precision temperature monitoring and could be applied at the cellular level.

SESELI LIBANOTIS (L.) W.D.J. KOCH (APIACEAE): CHEMICAL COMPOSITION OF ESSENTIAL OILS, THEIR ANTIBACTERIAL AND CYTOTOXIC ACTIVITIES

Introduction. Infectious diseases and cancer remain among the leading causes of death worldwide. In this regard, the search for biologically active molecules from among synthetic and natural compounds for the purpose of creating medicines remains an urgent task of modern science. Plants that have impressive natural and biotechnological resource potential, taking into account modern advances in the field of ex situ, in situ and in vitro cultiva-tion, remain a promising source of native substances. One of the promising sources of biologically active substances is a perennial plant, the Seseli libanotis (L.) W.D.J. Koch, Apiaceae, growing in central, eastern Europe and Asia in dry pastures and forest edges. The main components of the genus Seseli L. are furo- and pyranocoumarins, essential oils and polyacetylene compounds, which exhibit antibacterial, antifungal, insecticidal, diuretic, antiviral, anti-inflammatory, and antitumor properties. The aim – study of the chemical composition, antibacterial and cytotoxic activities of S. libanotis roots essential oil. Material and methods. The roots were collected in places of natural growth in September 2022, during the fruiting period (Irkutsk region, Maloye Goloustnoye village). The voucher specimen is stored in the herbarium of the Institute of Ecological Ecology SB RAS (UUH 020438). Obtaining essential oils. Essential oils were obtained by hydrodistillation. The qualitative composition and quantitative content of essential oil compo-nents were studied by GC/MS. The study of the antibacterial activity of essential oils was carried out in vitro on test cultures of gram-positive and gram-negative bacteria (Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Pseudomona saeruginosa, Salmonella enterica) using the disc diffusion method. Cell viability assay was performed on HeLa cell lines using trypan blue. Results. The composition and quantitative content of the components of essential oils of the roots of S. libanotis of the Baikal flora were studied for the first time. 28 components of predominantly monoterpene nature have been identified, the main ones being limonene (57,60%), α-pinene (6,88%), cis-β-ocimene (6,75%). Also found were fatty acids, polyacetylene-falcorinol and 7-isopen-tinyloxycoumarin. Essential oils of S libanotis have antibacterial activity against gram-positive bacteria Staphylococcus aureus, Streptococcus pyogenes and gram-negative bacteria Escherichia coli. Cultivation of Hela with S. libanotis essential oils resulted in decreased viability in the concentration range of 0.04–2.56 μL/mL for 72 hours. Conclusions. Essential oils of roots of S. libanotis, with high yield, containing falcarinol and coumarin, have antibacterial and cytotoxic activity.

Novel 5-(2-chloro-quinolin-3-yl)-[1,3,4]thiadiazol-2-ylamines and their copper(II) metallates: Preparation, spectroscopy, X-ray crystallography, nucleic acid/albumin binding, DNA cleavage and in vitro cytotoxicity

Copper(II) metallates of 2-chloroquinoline-3-carboxaldehyde-4(N)-substituted thiosemicarbazone (CuQ1, CuQ2, CuQ3, CuQ4) were synthesized, characterized by Fourier-Transform Infrared (FT-IR), Ultraviolet–Visible (UV–Vis), Electron Paramagnetic Resonance (EPR) and Mass spectrometry. The true nature of the ligands and a representative complex was confirmed by X-ray single crystal analysis. During the complexation, the ligands underwent cyclisation to form thiadiazole and two units of thiadiazole were coordinated to copper ion through N2-nitrogen atom. The remaining sites were occupied with two chloride ions and a water molecule which led to a square pyramidal geometry around copper ion. Absorption and emission titration methods confirmed the partial intercalative mode of binding interaction between CT-DNA and the metal complexes. The interaction between complexes and BSA led to the formation of ground state fluorophore-quencher complex by following static quenching mechanism. In vitro cytotoxic effect of the ligands and complexes were done by taking Human cervical cancer (HeLa) cells and toxicity of the test compounds were analyzed by using normal human kidney cell (HEK). The complexes CuQ2, CuQ3 and CuQ4 showed better cytotoxic activity against HeLa cells as compared with the standard cisplatin. Among the complexes, CuQ3 exhibited higher activity with least IC50 value (17 µM).

Structure-Based Discovery of Potential HPV E6 and EBNA1 Inhibitors: Implications for Cervical Cancer Treatment

Cervical cancer is the fourth most diagnosed cancer and the fourth leading cause of cancer death in women globally. Its onset and progression have been attributed to high-risk human papillomavirus (HPV) types, especially 16 and 18, while the Epstein–Barr virus (EBV) is believed to also significantly contribute to cervical cancer growth. The E6 protein associated with high-risk HPV strains, such as HPV16 and HPV18, is known for its role in promoting cervical cancer and other anogenital cancers. E6 proteins contribute to the malignant transformation of infected cells by targeting and degrading tumor suppressor proteins, especially p53. On the other hand, EBV nuclear antigen 1 (EBNA1) plays a crucial role in the maintenance and replication of the EBV genome in infected cells. EBNA1 is believed to increase HPV E6 and E7 levels, as well as c-MYC, and BIRC5 cellular genes in the HeLa cell line, implying that HPV/EBV co-infection accelerates cervical cancer onset and growth. Thus, the E6 and EBNA1 antigens of HPV and EBV, respectively, are attractive targets for cervical cancer immunotherapy. This study, therefore, virtually screened for potential drug candidates with good binding affinity to all three oncoviral proteins, HPV16 E6, HPV18 E6, and EBNA1. The compounds were further subjected to ADMET profiling, biological activity predictions, molecular dynamics (MD) simulations, and molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations. A total of six compounds comprising ZINC000013380012, ZINC000070454124, ZINC000014588133, ZINC000085568136, ZINC000095909247, and ZINC000085597263 demonstrated very strong affinity (≤−60 kJ/mol) to the three oncoviral proteins (EBNA1, HPV16 E6, and HPV18 E6) after being subjected to docking, MD, and MM/PBSA. These compounds demonstrated relatively stronger binding than the controls used, inhibitors of EBNA1 (VK-1727) and HPV E6 (baicalein and gossypetin). Biological activity predictions also corroborated their antineoplastic, p53-enhancing, Pin1 inhibitory, and JAK2 inhibitory activities. Further experimental testing is required to validate the ability of the shortlisted compounds to silence the insidious effects of HPV E6 and EBNA1 proteins in cervical cancers.

Isolation of flavonoids from Tagetes patula(French Marigold) flowers: Cytotoxic and oxidant activity in human cervical carcinoma cells

Tagetes patula, known as French Marigold, belongs to the family Asteraceae. Human papillomavirus infection is considered one of the causes of cervical cancer. This study assessedthe cytotoxic activity and intracellular oxidative capacity of compounds isolated from extract of T. patulaflowers as anti-cancer cervical agents. Fraction F6 of n-butanol extract was subjected to column chromatography and HPLC-ESI-MS. The isolated compounds of T. patulawere used to examine cytotoxic activity and the production of total reactive oxygen species in SiHa and HeLa cells; the cells were also characterized using scanning electron microscopy. Patulitrin was cytotoxic to SiHa and HeLa cells. An increase in ROS production was observed at different times of treatment of cells with patuletin and patulitrin. Scanning electron microscopy showed morphological changes in SiHa and HeLa cells. Thus, compounds isolated from T. patulahave great treatment potential against cervical cancer.

Delineating the Antiapoptotic Property of Apigenin as an Antitumor Agent: A Computational and In Vitro Study on HeLa Cells.

Apigenin, a flavonoid, is reported to have multiple health benefits including cancer prevention; this study evaluates the drug likeliness and Swiss ADME properties of apigenin. Apoptosis, which is a key hallmark of cancer, is associated with the deregulation of the balance between proapoptotic proteins and antiapoptotic proteins such as BCL-2,BCL-xl, BFL-1, BCL-w, BRAG-16, and MCL-1. The docking studies of apigenin with the mentioned proteins was performed to identify the interactions between the ligand and proteins, which suggested that apigenin was able to bind to most of the proteins similar to the inhibitory molecules of its native structure. A remarkable reduction in the total energy after energy minimization of apigenin-antiapoptotic protein complexes suggested increased stability of the docked complexes. The same complexes were found to be stable over a 10 ns period of molecular simulation at 300 K. These findings advocated the study to evaluate apigenin's potential to inhibit the HeLa cells at 5, 10, and 15 μM concentrations in the clonogenic assay. Apigenin inhibited the colony-forming ability of HeLa cells in a dose-dependent manner over a fortnight. Light microscopy of the treated cells displayed the morphological evidence characteristic of apoptosis in HeLa cells such as blebbing, spike formation, cytoplasmic oozing, and nuclear fragmentation. Thus, these results clearly indicate that apigenin may be used as a potential chemopreventive agent in cervical cancer management.

A “Turn-Off” Pyrene-Based Ligand as a Fluorescent Sensor for the Detection of Cu2+ and Fe2+ Ions: Synthesis and Application in Real Water Samples, Logic Gate Construction, and Bio-Imaging

Herein, we report the synthesis and characterization of a novel Schiff base ligand, (Z)-5-((pyren-1-ylmethylene)amino)-2,4-dihydro-3H-pyrazol-3-one (PMDP). The characterization of ligand PMDP was carried out using ESI-MS, 1H NMR, and UV–Visible spectroscopic techniques. As a probe, PMDP displayed a detectable, colorimetric colour shift in the presence of Cu2+ and Fe2+ ions. The solution was seen to have a light brown colour and to exhibit a fluorometric “turn off” response when Cu2+ and Fe2+ ions were present in a DMSO solution (HEPES 0.01 M, pH = 7.4) at room temperature. Job’s plot revealed that the PMDP binding ratio to Cu2+ and Fe2+ ions was in 1:2 ratio. In contrast to the other metal ions (Cd2+, Mn2+, Co2+, Na+, Ni2+, Cu+, Fe3+, Hg2+, Mg2+, Zn2+, K+, and V5+), the synthesised probe showed exceptional sensitivity and selectivity for detecting Cu2+ and Fe2+ metal ions. The results indicate that the detection limits for Cu2+ and Fe2+ are 0.42 μM and 0.51 μM, respectively. Furthermore, PMDP was efficiently utilised for the quantitative analysis of Cu2+ and Fe2+ in real water samples, RGB colour values in smart phones, logic gate construction, and cell imaging in HeLa cells.

Synthesis, characterisation, X-ray diffraction and biological evaluation of new thiourea derivatives against Mycobacterium tuberculosis and cervical cancer

In this study, thiourea derivatives were prepared to identify potentially effective compounds against tuberculosis and cervical cancer. The newly synthesized compounds, namely N-(cyclohexyl(methyl)carbomothioyl) benzamide (TU1), N-(cyclohexyl(methyl)carbamothioyl)-2-methylbenzamide (TU2), N-(dicyclohexylcarbamothioyl) benzamide (TU3), N-(dicyclohexylcarbamothioyl)-4-nitrobenzamide (TU4), N-(diphenylcarbamothioyl) benzamide (TU5), and N-(diphenylcarbamothioyl)-4-nitrobenzamide (TU6), were obtained in high purity and yields. The compounds were successfully characterized by infrared spectroscopy (IR), ultraviolet-visible spectroscopy (UV-Vis), nuclear magnetic resonance (NMR), single crystal X-ray diffractometer (SCXRD), mass spectrometry (MS) and the melting points (mp). Crystal structure analyses of TU1, TU2 and TU6 were carried out which showed, that in the solid state, the molecules were linked together by intermolecular hydrogen bonds, specifically NH⋯S and CH⋯O interactions. In-vitro testing against M. tuberculosis (Mtb) revealed compounds TU1 and TU2 to be the most potent with MIC90 values of 28.2 and 11.2 μM, respectively. However, compounds TU4, TU5, and TU6, with MIC90 values of 80.3, 82.8 and 107.7 µM, respectively, exhibit mild antituberculosis activity, whereas TU3 with a MIC90 value of 752.7 µM is considered inactive against the Mtb strain. None of the compounds demonstrated significant selectivity for bacterial cells versus human cells and thus further studies could be dedicated to creating derivatives of TU1 and TU2 that are more selective. In vitro biological screening against HeLa cells revealed two highly toxic compounds, TU2 and TU6, with respective IC50 values of 12.00 ± 1.21 μM (SI = 1.06) and 8.45 ± 1.21 μM (SI = 0.08); and two moderately toxic compounds, TU4 (IC50 = 27.75 ± 1.15 µM; SI = 0.35) and TU5 (IC50 = 23.66 ± 1.24 µM; SI = 0.29).

H3.3-G34W in giant cell tumor of bone functionally aligns with the exon choice repressor hnRNPA1L2.

RNA processing is an essential post-transcriptional phenomenon that provides the necessary complexity of transcript diversity prior to translation. Aberrations in this process could contribute to tumourigenesis, and we have previously reported increased splicing alterations in giant cell tumor of bone (GCTB), which carries mutations in the histone variant H3.3 encoding glycine 34 substituted for tryptophan (H3.3-G34W). G34W interacts with several splicing factors, most notably the trans-acting splicing factor hnRNPA1L2. To gain a deeper understanding of RNA processing in GCTB and isogenic HeLa cells with H3.3-G34W, we generated RNA-immunoprecipitation sequencing data from hnRNPA1L2 and H3.3-G34W associated RNAs, which showed that 80% overlapped across genic regions and were frequently annotated as E2F transcription factor binding sites. Splicing aberrations in both GCTB and HeLa cells with H3.3-G34W were significantly enriched for known hnRNPA1L2 binding motifs (p value < 0.01). This splicing aberration differed from hnRNPA1L2 knockouts, which showed alterations independent of H3.3-G34W. Of functional significance, hnRNPA1L2 was redistributed to closely match the H3.3 pattern, likely driven by G34W, and to loci not occupied in normal parental cells. Taken together, our data reveal a functional overlap between hnRNPA1L2 and H3.3-G34W with likely significant consequences for RNA processing during GCTB pathogenesis. This provides novel opportunities for therapeutic intervention in future modus operandi.

Mutation in PDGFRbeta: a potential new pathogenic variant for acquired mitral valve prolapse

Abstract Funding Acknowledgements None. Background Mitral valve prolapse (MVP) due to myxomatous degeneration is characterized by familial clustering, but few pathogenic genes have been identified. In a genetic screening program for MVP patients, we identified a platelet-derived growth factor receptor β (PDGFRβ)-E162K missense variant in a family with a bi-leaflet MVP phenotype in four affected family members. PDGFRβ is a receptor tyrosine kinase, which plays an important role in vascular development. Purpose In this study, we investigated whether the E162K substitution in PDGFRβ could lead to mitral valve abnormalities. Methods To assess the functional effects of the missense variant, proliferation and migration assays were performed using HeLa cells overexpressing wild-type (WT) or mutant PDGFRβ. Immunostainings were performed to determine PDGFRβ expression in the diseased valves from a family member undergoing surgical operation and from additional patients operated for MVP. Mouse models were created with the mouse equivalent of the human PDGFRβ-E162K variant (PDGFRβ-E161K) using CRISPR/CAS9. The variant was not lethal and transthoracic echocardiography was performed on adult homozygous PDGFRβE161K/E161K mice, heterozygous PDGFRβE161K/- mice, and WT mice . In addition, histology was performed in adult and neonatal mice to detect potential valvular defects. Results HeLa cells expressing PDGFRβ-E162K and stimulated with PDGFD showed reduced proliferation and migration, suggesting a loss of function of the mutant receptor. PDGFRβ was expressed in human diseased mitral valves. Echocardiographic evaluation revealed a significant larger mitral valve annulus diameter in both PDGFRβE161K/- and PDGFRβE161K/E161K compared to WT (WT: 1.97 mm; PDGFRβE161K/-:2.13, p=0.031; PDGFRβE161K/E161K:2.42 mm, p&amp;lt;0.0001). Histological data in PDGFRβE161K/E161K mice showed significant leaflet thickening in the free edge (FE) of the posterior mitral valve leaflet (PMVL) compared to WT (WT: 72.34 ɥm; PDGFRβE161K/E161K: 109.6 ɥm, p=0.040) and a larger leaflet area of the PMVL compared to WT (WT: 25280 ɥm²; PDGFRβE161K/E161K: 44494 ɥm², p=0.020). Moreover, an altered organization of the extracellular matrix reminiscent of the myxomatous degeneration in MVP was observed. These alterations were not observed in mutant neonatal hearts. Conclusions The PDGFRβ-E162K variant is associated with familial MVP and alters the function of PDGFRβ. Mice harboring this mutation display acquired mitral valve defects.

The Polysaccharides from Pinellia ternata and Their Derivatives: Preparation, Structure Characteristics, and Activities in Vitro.

Three polysaccharides, PTC, PTH, and PTB, were extracted from Pinellia ternata using three different extraction conditions: room temperature water, hot water, and 2 % Na2CO3 solution. PTC and PTH were composed of rhamnose, glucose, galactose, mannose, glucuronic acid, galacturonic acid, and arabinose, which combine to form complex structures. PTB was composed solely of glucose and rhamnose. Further analysis indicated that PTC and PTB exhibited triple-helix structures. PTC showed the highest scavenging capacity against DPPH, superoxide anion, and hydroxyl radicals, with half maximal inhibitory concentrations (IC50) of 1004.1, 1584.1, and 1584.1 μg/mL, respectively. Additionally, PTC, PTH, and PTB were subjected to sulfation, phosphorylation, and selenization, resulting in the production of nine derivates. The distinctive absorptive bands of these derivates were determined through infrared spectroscopy. Selenized and sulfated derivates have shown significant antitumor and immunoenhancing properties. Our findings revealed that at 400 μg/mL, the inhibition rate of selenated PTB on HeLa cells was 54.2 % and that on HepG2 cells was 43.1 %. Additionally, selenized PTC displayed significant immunoenhancing activity, with a proliferation rate of 63.7 % at 400 μg/mL in RAW264.7 cells. These results provide valuable evidence supporting the consideration of polysaccharides from Pinellia ternata as a potential candidate for the development of antineoplastic drugs.

In Vitro Biological and GC-MS Analysis of Whole Plant Calotropis procera

Calotropis procera is a medicinal, traditional, and therapeutic plant in Pakistan. In this research study, the biological activities, for instance, anticancer, antileishmanial, antibacterial, antifungal, anti-inflammatory, and brine shrimp lethality assay and GC-MS are studied. MTT assay, antileishmanial bioassay, microplate Alamar Blue assay, agar tube dilution method, oxidative burst assay using chemiluminescence technique, B-hatching techniques, and triple quadrupole acquisition method MS parameters were the methods used for anticancer, antileishmanial, antibacterial, antifungal, anti-inflammatory, brine shrimp lethality assay, and gas chromatography-mass spectrometry. Whole plant methanol extract of Calotropis procera (WMECP) inhibited 69.1% of the growth of HeLa cell line with an IC50 value of 3.1 ± 0.4 and whole plant n-hexane fraction of Calotropis procera (WHFCP) and whole plant and aqueous fraction of Calotropis procera (WAFCP) inhibited the growth by 70.2% and 65.2% with IC50 values of 5.0 ± 0.3 and 17.1 ± 1.0. Whole plant methanol extract of Calotropis procera (WMECP) inhibited 70.1% of the growth of the PC3 cell line with an IC50 value of 5.1 ± 0.3 and whole plant n-hexane fraction of Calotropis procera (WHFCP) and whole plant aqueous fraction of Calotropis procera (WAFCP) inhibited 61.6% and 59.7% with IC50 values of 3.7 ± 0.5 and 16.4 ± 1.0. None of the extract and fractions of Calotropis procera showed anticancer activities against the 3T3 cell line. None of the extract and fractions of Calotropis procera showed antileishmanial, antibacterial, antifungal, and anti-inflammatory activities. Whole plant methanol extract of Calotropis procera (WMECP) exhibited lethality at the highest concentration while other fractions did not exhibit lethality. GC-MS studies revealed that the whole plant methanol extract of Calotropis procera (WMECP) consists of 11 compounds, whole plant n-hexane fraction of Calotropis procera (WHFCP) consists of 9 compounds, and whole plant aqueous fraction of Calotropis procera (WAFCP) consists of 7 compounds.

Characterization and Engineered U1 snRNA Rescue of Splicing Variants in a Turkish Neurodevelopmental Disease Cohort

Although they are rare in the population, rare neurodevelopmental disorders (RNDDs) constitute a significant portion of all rare diseases. While advancements in sequencing technologies led to improvements in diagnosing and managing rare neurodevelopmental diseases, accurate pathogenicity classification of the identified variants is still challenging. Sequence variants altering pre-mRNA splicing make up a significant part of pathogenic variants. Despite advances in the in silico prediction tools, noncanonical splice site variants are one of the groups of variants that pose a challenge in their clinical interpretation. In this study, we analyzed the effects of seven splicing variants we had previously proposed as disease-causing and demonstrated that all but one of the seven variants had a strong or moderate effect on splicing, as assessed by a minigene assay. Next, applying U1 snRNAs engineered for different splicing variants in the corresponding genes and expressed with minigene plasmids in HeLa cells provided a partial correction in four of the studied genes to varying degrees. Findings from our study highlight the importance of in vitro minigene-based assays for the reclassification of putative splice-altering variants of uncertain significance and the therapeutic potential of modified U1 snRNAs in RNDDs.

Sodium copper chlorophyllin conjugated with Ag plasmonic nanoparticles as efficient nanostructure for application in photodynamic therapy

Photodynamic therapy (PDT) is a method that uses light-sensitive photosensitizers to stimulate cells with specific wavelengths. Nanoparticles (NPs) are an emerging technology in PDT, offering advantages over classical photosensitizers. The amalgamation of silver NPs and photosensitizer drugs has gained significant attention in PDT. We conjugated Ag NPs to sodium-copper chlorophyllin (SCC) in this research. The binding of Ag NPs to SCC was examined using X-ray diffraction, SEM, EDS, DLS, Zeta potential, and FTIR analyses. The optical properties of SCC before and after binding toAg NPs were performed through Photoluminescence (PL) analysis and UV–visible spectroscopy, as well as the production of reactive oxygen species (ROS) and free radicals (hydroxyl radical) before and after binding through the photobleaching phenomenon of methylene blue and photochemical degradation of anthracene. SCC exhibits high absorption in the visible spectrum violet-blue (350–470 nm) and red (570–710 nm) regions. HeLa cells and red LED were used to investigate the cytotoxicity (MTT assay) of SCC attached to Ag NPs.

Euonymus hamiltonianus Extract Improves Amnesia in APPswe/Tau Transgenic and Scopolamine-Induced Dementia Models.

Dementia is a syndrome exhibiting progressive impairments on cognition and behavior beyond the normal course of aging, and Alzheimer's disease (AD) is one of the neurodegenerative diseases known to cause dementia. We investigated the effect of KGC07EH, the 30% ethanol extract of Euonymus hamiltonianus, against amyloid-β (Aβ) production and cognitive dysfunction in dementia models. KGC07EH was treated on Hela cells expressing the Swedish mutant form of amyloid precursor protein (APP), and the AD triple transgenic (3× TG) mice were given KGC07EH orally during 11-14 months of age (100 and 300mg/kg/day). SH-SY5Y cell line was used to test KGC07EH on scopolamine-induced elevation of acetylcholinesterase (AChE) activity. ICR mice were intraperitoneally injected with scopolamine, and KGC07EH was administered orally (50, 100, and 200mg/kg/day) for 4 weeks. KGC07EH treatment decreased Aβ, sAPPβ-sw, and sAPPβ-wt levels and APP protein expressions while sAPPα was increased in Swedish mutant-transfected HeLa cells. KGC07EH treatment also significantly reduced the accumulation of Aβ plaques and tau tangles in the brain of 3× TG mice as well as improving the cognitive function. In SH-SY5Y cells cultured with scopolamine, KGC07EH dose-dependently attenuated the increase of AChE activity. KGC07EH also improved scopolamine-induced learning and memory impairment in scopolamine-injected mice, and in their cerebral cortex and hippocampus, the expression levels of p-ERK, p-CREB, p-Akt, and BDNF were attenuated. KGC07EH inhibits APP processing and Aβ production both in vitro and in vivo, while enhancing acetylcholine signaling and cognitive dysfunction which are the major symptoms of dementia.

Curcuminoid PBPD induces cuproptosis and endoplasmic reticulum stress in cervical cancer via the Notch1/RBP-J/NRF2/FDX1 pathway.

Curcumin has been shown to have antitumor properties, but its low potency and bioavailability has limited its clinical application. We designed a novel curcuminoid, [1-propyl-3,5-bis(2-bromobenzylidene)-4-piperidinone] (PBPD), which has higher antitumor strength and improves bioavailability. Cell counting kit-8 was used to detect cell activity. Transwell assay was used to detect cell invasion and migration ability. Western blot and quantitative polymerase chain reaction were used to detect protein levels and their messenger RNA expression. Immunofluorescence was used to detect the protein location. PBPD significantly inhibited the proliferation of cervical cancer cells, with an IC50 value of 4.16 μM for Hela cells and 3.78 μM for SiHa cells, leading to the induction of cuproptosis. Transcriptome sequencing analysis revealed that PBPD significantly inhibited the Notch1/Recombination Signal Binding Protein for Immunoglobulin kappa J Region (RBP-J) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways while upregulating ferredoxin 1 (FDX1) expression. Knockdown of Notch1 or RBP-J significantly inhibited NRF2 expression and upregulated FDX1 expression, leading to the inhibition of nicotinamide adenine dinucleotide phosphate activity and the induction of oxidative stress, which in turn activated endoplasmic reticulum stress and induced cell death. The overexpression of Notch1 or RBP-J resulted in the enrichment of RBP-J within the NRF2 promoter region, thereby stimulating NRF2 transcription. NRF2 knockdown resulted in increase in FDX1 expression, leading to cuproptosis. In addition, PBPD inhibited the acidification of tumor niche and reduced cell metabolism to inhibit cervical cancer cell invasion and migration. In conclusion, PBPD significantly inhibits the proliferation, invasion, and migration of cervical cancer cells and may be a novel potential drug candidate for treatment of cervical cancer.

Design, concise synthesis and evaluation of novel amide-based combretastatin A-4 analogues as potent tubulin inhibitors

As our ongoing work, a novel series of the amide-based CA-4 analogues were successfully designed, synthesized, and explored for their biological evaluation. Among these compounds, 7d and 8a illustrated most potent antiproliferative activity toward A549, HeLa, HCT116, and HT-29 cell lines. Most importantly, these two compounds didn’t display noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies revealed that analogue 8a was identified as a novel tubulin polymerization inhibitor with an IC50 value of 6.90 μM, which is comparable with CA-4. The subsequent investigations unveiled that analogue 8a not only effectively caused cell cycle arrest at the G2/M phase but also induced apoptosis in A549 cells via a concentration-dependent manner. The molecular docking revealed that 8a could occupy well the colchicine-binding site of tubulin. Collectively, these findings indicate that amide-based CA-4 scaffold could be worthy of further evaluation for development of novel tubulin inhibitors with improved safety profile.

Environment friendly MOF-MoS2 composite for Cr(VI) and Pb(II) capture from paint industry wastewater: sequestration, regeneration and toxicity

Treatment of paint industry wastewater is challenging due to the presence of interfering ions, tertiary organics and radical species beyond acceptable levels. Further, the synthetic nature of adsorbent poses a risk in post-adsorption waste disposal due to hightened chances of environmental damage or toxicity. Therefore, this reported study focuses on the development of an ecofriendly heterogeneous composite by hydrothermal process using Iron-terephthalic acid (BDC), Metal-organic framework (MOF), and Molybdenum disulphide (MoS2)-together named Fe(BDC)-MoS2. This composite was tested for adsorption of Cr(VI) available in paint industry effluent wastewater (PW). The characterization of the Fe(BDC)-MoS2 using SEM, XRD, XPS, FTIR, revealed resilient formation of the composite. The maximum adsorption capacity (qmax) for Cr(VI) was 116.36 mg/g at 1.0 g/L Fe(BDC)-MoS2 dose at pH 5.13. Fe(BDC)-MoS2 readily adsorbed Cr(VI) from PW with ∼ 99.99 % effecieny. Significant reduction in the co-existing cations (e.g., Ni2+, Mn3+, Al3+, Cu2+, Co2+, Pb2+, and Zn2+) and anions (e.g. Chloride, Sulfate, and Nitrate) was also observed. The reusability study demonstrated a drop in adsorption efficiency by about 25 % after 4 consecutive cycles. The toxicity study on the human cervical epithelial (HeLa) cells at 50 μg/m Fe(BDC)-MoS2 dose showed cell viability of 95, while at 250 μg/Ml, it was 26.5 %. Overall, this study demonstrated Fe(BDC)-MoS2 as an ecofriendly and viable adsorbent for treating industrial wastewater.

Unveiling the anti-vitiligo, anti-inflammatory, and antitumor activities of sesquiterpene coumarins isolated from Ferula kuhistanica

Six undescribed bicyclic sesquiterpene coumarins, kuhistanin A, ferukrin isovalerate, 9’β,12’α - ferukrin isovalerate, (17′E)- 9’α, 12’β - isomarcandin, (17′Z)- 9’α, 12’β - isomarcandin and (17′E) - isomarcandin, together with nine known ones were isolated from the roots of Ferula kuhistanica Korovin. The structures of them were elucidated using NMR and HRESIMS data analysis. The relative configurations of the isolates were confirmed by NOE correlations and NMR calculation. The absolute configurations of them were confirmed by X-ray diffraction analysis and ECD calculation. Anti-vitiligo, anti-inflammatory and cytotoxicity of the isolates were tested. Acetyl feselol, feselol, ferusingensine I and farnesiferol A significantly increased the melanin content at the concentration of 10 μM. (17′E) - 9’α, 12’β - isomarcandin exhibited strong cytotoxicity against HT-29 cell line with IC50 values of 8.94 ± 0.47 μM, and (17′E) - isomarcandin demonstrated strong cytotoxicity against Hela, A549 and HT-29 cell lines with IC50 values of 5.29 ± 0.25, 4.01 ± 0.20, and 4.16 ± 0.21 μM, respectively. This study concluded that, isolated compounds from F. kuhistanica demonstrated strong bioactivity towards anti-vitiligo and cytotoxicity and active compounds are suggested as anti-vitiligo and cytotoxicity agent for future drug development.

Furostanol glycosides, stilbenoids and nucleosides from the roots of Smilax perfoliata, and evaluation of their cytotoxic and anticholinesterase activities

Three undescribed compounds including two furosteroid glycosides (perfoloside and 22-O-methylperfoloside) and one stilbenedimer (perfolostilbene) together with 21 known compounds were isolated from the roots of Smilax perfoliata. The structural elucidation was established by extensive uses of HRMS, 1D and 2D spectroscopic techniques. The assignment of the stereocenters in perfolostilbene was based on NOESY data and ECD calculation. Among the isolates, two compounds showed marginal cytotoxic activity against KB and Hela cell lines while seven stilbenoids showed strong to weak antiacetylcholinesterase and antibutyrylcholinesterase activities with IC50 ranging between 2–197 µM.