Sulfated Polyhydroxysteroid Glycosides from the Sea of Okhotsk Starfish Henricia leviuscula spiculifera and Potential Mechanisms for Their Observed Anti-Cancer Activity against Several Types of Human Cancer Cells.

Three new monosulfated polyhydroxysteroid glycosides, spiculiferosides A (1), B (2), and C (3), along with new related unsulfated monoglycoside, spiculiferoside D (4), were isolated from an ethanolic extract of the starfish Henricia leviuscula spiculifera collected in the Sea of Okhotsk. Compounds 1-3 contain two carbohydrate moieties, one of which is attached to C-3 of the steroid tetracyclic core, whereas another is located at C-24 of the side chain of aglycon. Two glycosides (2, 3) are biosides, and one glycoside (1), unlike them, includes three monosaccharide residues. Such type triosides are a rare group of polar steroids of sea stars. In addition, the 5-substituted 3-OSO3-α-L-Araf unit was found in steroid glycosides from starfish for the first time. Cell viability analysis showed that 1-3 (at concentrations up to 100 µM) had negligible cytotoxicity against human embryonic kidney HEK293, melanoma SK-MEL-28, breast cancer MDA-MB-231, and colorectal carcinoma HCT 116 cells. These compounds significantly inhibited proliferation and colony formation in HCT 116 cells at non-toxic concentrations, with compound 3 having the greatest effect. Compound 3 exerted anti-proliferative effects on HCT 116 cells through the induction of dose-dependent cell cycle arrest at the G2/M phase, regulation of expression of cell cycle proteins CDK2, CDK4, cyclin D1, p21, and inhibition of phosphorylation of protein kinases c-Raf, MEK1/2, ERK1/2 of the MAPK/ERK1/2 pathway.

Granulation Patterns of Functional Corticotroph Tumors Correlate with Tumor Size, Proliferative Activity, T2 Intensity-to-White Matter Ratio, and Postsurgical Early Biochemical Remission.

Unlike somatotroph tumors, the data on correlates of tumor granulation patterns in functional TPIT lineage pituitary neuroendocrine tumors (corticotroph tumors) have been less uniformly documented in most clinical series. This study evaluated characteristics of 41 well-characterized functional corticotroph tumors consisting of 28 densely granulated corticotroph tumors (DGCTs) and 13 sparsely granulated corticotroph tumors (SGCTs) with respect to preoperative clinical and radiological findings, tumor proliferative activity (including mitotic count and Ki-67 labeling index), and postoperative early biochemical remission rates. The median (interquartile range (IQR)) tumor size was significantly larger in the SGCT group [16.00 (16.00) mm in SGCT vs 8.5 (9.75) mm in DGCT, p = 0.049]. T2-weighted signal intensity and T2 intensity (quantitative) did not yield statistical significance based on tumor granulation; however, the T2 intensity-to-white matter ratio was significantly higher in SGCTs (p = 0.049). The median (IQR) Ki-67 labeling index was 2.00% (IQR 1.00%) in the DGCT group and 4.00% (IQR 7.00%) in the SGCT group (p = 0.043). The mitotic count per 2 mm2 was higher in the SGCT group (p = 0.001). In the multivariate analysis, the sparse granulation pattern (SGCT) remained an independent predictor of a lower probability of early biochemical remission irrespective of the tumor size and proliferative activity (p = 0.012). The current study further supports the impact of tumor granulation pattern as a biologic variable and warrants the detailed histological subtyping of functional corticotroph tumors as indicated in the WHO classification of pituitary neuroendocrine tumors. More importantly, the assessment of the quantitative T2 intensity-to-white matter ratio may serve as a preoperative radiological harbinger of SGCTs.

Chemical Constituents with Anti-Proliferative Activity on Pulmonary Arterial Smooth Muscle Cells from the Roots of Anthriscus sylvestris (L.) Hoffm.

A chemical investigation of Anthriscus sylvestris roots led to the isolation and characterization of two new nitrogen-containing phenylpropanoids (1-2) and two new phenol glycosides (8-9), along with fifteen known analogues. Structure elucidation was based on HRESIMS, 1D and 2D NMR spectroscopy, and electronic circular dichroism (ECD). In addition, compounds 3, 6, 9-10, 12, and 17 exhibited inhibitory effects against the abnormal proliferation of pulmonary arterial smooth muscle cells with IC50 values ranging from 10.7 ± 0.6 to 57.1 ± 1.1 µM.

Whey Protein Sodium-Caseinate as a Deliverable Vector for EGCG: In Vitro Optimization of Its Bioaccessibility, Bioavailability, and Bioactivity Mode of Actions.

Epigallocatechin gallate (EGCG), the principal catechin in green tea, exhibits diverse therapeutic properties. However, its clinical efficacy is hindered by poor stability and low bioavailability. This study investigated solid particle-in-oil-in-water (S/O/W) emulsions stabilized by whey protein isolate (WPI) and sodium caseinate (NaCas) as carriers to enhance the bioavailability and intestinal absorption of EGCG. Molecular docking revealed binding interactions between EGCG and these macromolecules. The WPI- and NaCas-stabilized emulsions exhibited high encapsulation efficiencies (>80%) and significantly enhanced the bioaccessibility of EGCG by 64% compared to free EGCG after simulated gastrointestinal digestion. Notably, the NaCas emulsion facilitated higher intestinal permeability of EGCG across Caco-2 monolayers, attributed to the strong intermolecular interactions between caseins and EGCG. Furthermore, the emulsions protected Caco-2 cells against oxidative stress by suppressing intracellular reactive oxygen species generation. These findings demonstrate the potential of WPI- and NaCas-stabilized emulsions as effective delivery systems to improve the bioavailability, stability, and bioactivity of polyphenols like EGCG, enabling their applications in functional foods and nutraceuticals.

Phosphatidylcholine and ceramide derivatives from white rot fungus Microporus xanthropus PP17-20.

The undescribed phosphatidylcholine (1), along with twelve known compounds, was isolated from the cultures of white rot fungus Microporus xanthropus PP17-20. In this work the fungus was cultivated in Yeast-Malt extract medium to explore active compound production. The chemical structures were elucidated on the basis of spectroscopic and HRESIMS data. Several isolated compounds were evaluated for anti-proliferative activity against A549 and MCF-7 cancer cell lines.

Novel synthesis of the first new class of triazine sulfonamide thioglycosides and the evaluation of their anti-tumor and anti-viral activities against human coronavirus.

Novel class of triazine sulfonamide thioglycosides was designed and synthesized. Those novel structures comprising three essential and pharmacological significant moieties such as the triazine, sulfonamide, and thioglycosidic scaffolds. The triazine sulfonamides were furnished via a direct approach starting from potassium cyanocarbonimidodithioate, then the corresponding triazine sulfonamide thioglycosides were generated using the peracylated α-d-gluco- and galacto-pyranosyl bromides. Anti-viral evaluation of compounds in vitro against HCoV-229E virus revealed that some compounds possess promising activity. Compounds 4a, 4b, 4d, 6d and 6e indicate from moderate to low antiviral activity against low pathogenic coronavirus 229E in comparison with remdesivir at a concentration of 100 µg/mL. Additionally their in vitro anti-proliferative effects against NCI 60 cancer cell lines cell lines were also investigated. Compound 4a, the most potent compound among the estimated compounds, revealed remarkably lowest cell growth promotion against CNS cancer SNB-75, and renal cancer UO-31.

An in vitro nevus explant model for studying the effects of ultraviolet radiation.

Ultraviolet radiation (UVR) has been recognized as a potential trigger for the transformation of benign melanocytic nevi into melanoma. However, the mechanisms governing the formation and progression of melanocytic nevi remain poorly understood. This lack of understanding is partly due to the difficulty in isolating and culturing nevus tissues in vitro, resulting in a dearth of robust ex vivo models for nevi. Therefore, the establishment of a reliable melanocytic nevus model is imperative. Such a model is essential for elucidating nevus pathogenesis and facilitating the development of effective therapeutic interventions. Therefore, we have sought to establish an ex vivo nevus explant model to study UVR stimulation. And the structural integrity and tissue activity of the ex vivo nevi explant model was evaluated. We then observed melanogenesis and proliferation activity of the explants after UVR stimulation. There was less blister formation after Day 3 in nevi explants under our modified medium conditions. The nevi explant was able to maintain almost the same morphological structure and tissue activity as in vivo tissue within 24 h. Following UVR stimulation, we observed increased melanogenesis and proliferation activity in nevi explants. Nevi explants could serve as an ex vivo model for UVR-induced nevi stimulation research.

Development of new steroid-based hydrazide and (thio)semicarbazone compounds with anticancer properties.

Most breast and prostate cancers are caused by abnormal production or action of steroidal hormones. Hormonal drugs based on steroid scaffolds represent a significant class of chemotherapeutics that are routinely used in chemotherapy. In this study, the synthesis of new 17a-homo lactone and 17α-(pyridine-2-ylmethyl) androstane derivatives with hydrazide and semicarbazone motifs is presented. All compounds were screened for their effect on cell viability against a panel of five cancer cell lines and one healthy cell line. Two compounds showed significant cytotoxicity against cancer cells, with low toxicity against healthy cells. The relative binding affinities of compounds for the ligand-binding domains of estrogen receptor α, estrogen receptor ß, androgen receptor and glucocorticoid receptor were tested using a fluorescence screen in yeast. Potential for inhibition of aldo-keto reductase 1C3 and 1C4 activity was measured in vitro. Experimental results are analyzed in the context of molecular docking simulations. Our results could help guide design of steroid compounds with improved anticancer properties against androgen- and estrogen-dependent cancers.

Alkaloids from Zanthoxylum nitidum and their anti-proliferative activity against A549 cells by regulating the EGFR/AKT/mTOR pathway.

Zanthoxylum nitidum is frequently used as a traditional Chinese medicine and food supplement. Our previous study revealed that its constituent compounds were able to inhibit cancer cell proliferation. In our continuous exploration of bioactive compounds in Z. nitidum, we isolated ten alkaloids (1-10), including one new natural compound (1), and nine known alkaloids (2-10), from an ethanolic extract of the whole plant. The chemical structures were elucidated based on a combination of comprehensive NMR and HRESIMS analyses. Compounds 5, 8 and 10 exhibited significant antiproliferative effects against A549 cancer cell lines. We further elucidated the underlying molecular mechanisms of the antiproliferative activity of compound 8 in A549 human lung cancer cells. Compound 8 was found to induce cell cycle arrest in the G0/G1 phase via p53 activation and CDK4/6 suppression. Compound 8 also effectively inhibited cell migration through the modulation of the epithelial-mesenchymal transition (EMT), as indicated by the expression of biomarkers, such as N-cadherin downregulation and E-cadherin upregulation. Compound 8 significantly suppressed the activation of the EGFR/AKT/mTOR signalling pathway in A549 cells. These results indicate that alkaloid 8 from Z. nitidum has potential to be a lead antiproliferative compound in cancer cells.

Approaches Towards Better Immunosuppressive Agents.

Several classes of compounds are applied in clinics due to their immunosuppressive properties in transplantology and the treatment of autoimmune diseases. Derivatives of mycophenolic acid, corticosteroids and chemotherapeutics bearing heterocyclic moieties like methotrexate, azathioprine, mizoribine, and ruxolitinib are active substances with investigated mechanisms of action. However, improved synthetic approaches of known drugs and novel derivatives are still being reported to attempt better accessibility and therapeutic properties. In this review article, we present the synthesis of the designed chemical structures based on recent literature reports concerning novel compounds as promising immunosuppressive drugs. Moreover, some of the discussed derivers revealed also other types of activities with prospective medicinal potential.

A New Rare Halogenated Depside from Lichen and Study of its Anti-Proliferative Activity.

Lichens are a symbiotic association of algae and fungus, belonging to the family Parmeliaceae. Some lichen species are edible and used as an active ingredient for preparation of exotic spices as well as folklore medicine to cure different kinds of ailments. A specimen of lichen was collected from Munner in the Kerala State of South India for chemical profiling. Chemical analyses of the diethyl ether extract of the defatted lichen led to the isolation of six phenols 1-6 with variation of relative abundance. Amongst them, the relative abundance of compound 3 was the greatest (1 % of crude extract) and it was identified as atranorin. The structures of known compounds were confirmed by comparison of their 1H-NMR, 13C NMR, and mass data with published values available in the literature. In vitro bioassay for anti-proliferative activity of these compounds has been conducted against various human cancer cell lines in comparison with paclitaxel as control using SRB assay. Interestingly, a new compound 5 was found along with previously reported compounds from this lichen. This new compound was designated as fluoroatranorin 5 which was reported for the first time herein. The structural characterization of a new depside was determined by spectral methods such as 1H-NMR, 13C NMR, 19F NMR, IR, LC-HRESI-MS, and LC-MS/MS study. Its structure was confirmed by single crystal X-ray diffraction study. This new compound was designated as fluoroatranorin 5 which was reported first time herein. Anti-proliferative activity of all these compounds was evaluated against six different cancer cell lines. The inhibitory activity, IC50 value of compounds 1-3 and 5 exhibited at 99.64, 102.04, 109.20, 53.0 and 2.4 µM on cancer cell lines HT-29 (colon), Hela (cervical), HT-29, HPAC (pancreas) and A2780 (ovarian cancer cell line) respectively in comparison with paclitaxel as control. The new compound 5 exhibited significant activity with IC50 value 2.4 µM on A2780 ovarian cancer cell line.

Association Between Multiple Single Nucleotide Polymorphisms in Folate Metabolism Pathway and Breast Cancer Risk in Georgian Women: A Case-Control Study.

Background: The folate metabolism pathway plays an integral part in DNA synthesis, methylation, and repair. Methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD1) are both enzymes that are involved in this pathway, and the single nucleotide polymorphisms (SNPs) in genes coding for them have modulatory effects on DNA expression. This study aimed to investigate the relationship between MTHFR C677T (rs1801133) and MTHFD1 G1958A (rs2236225) polymorphisms and the risk of developing breast cancer in Georgian women. Methods: A case-control study was performed examining the MTHFR C677T and MTHFD1 G1958A SNP in breast cancer-confirmed cases and healthy matched controls. Real time-polymerase chain reaction (PCR) was used to genotype SNPs. The case individuals' pathology reports were obtained following surgeries for cancer characteristic data. Statistical analysis was performed to investigate the significance of the acquired data. Results: Statistical analysis of MTHFR C677T SNP revealed that the CT genotype increased the risk of breast cancer by 2.17 folds in the over-dominant model. Statistical analysis of MTHFD1 G1958A SNP showed that the GA genotype increased the risk of breast cancer by 4.12 folds in the codominant model and 2.41 folds in the over-dominant model. No statistically significant link was found between genotypes and lymph node status, however, patients with the CT genotype had higher percentages of proliferative activity. Conclusions: Breast cancer seems to have a statistically significant association with the CT genotype in MTHFR C677T and the GA genotype in MTHFD1 G1958A in Georgian women.

Discovery of novel pyrrolo[2,3-d]pyrimidines as potent menin-mixed lineage leukemia interaction inhibitors.

To interfere the Menin-MLL interaction using small molecular inhibitors has been shown as new treatment of several special hematological malignancies. Herein, a series of Menin-MLL interaction inhibitors with pyrrolo[2,3-d]pyrimidine scaffold were designed, synthesized and evaluated. Among them, compound A6 exhibited potent binding affinity with an IC50 value of 0.38 µM, and strong anti-proliferative activity against MV4-11 cells with an IC50 value of 1.07 µM. Further study showed A6 reduced the transcriptional levels of HOXA9 and MEIS1 genes. Moreover, A6 induced cellular apoptosis, arrested the cell cycle in G0/G1 phase, and reversed the differentiation arrest in a concentration-dependent manner. This study suggested compound A6 was as a novel potent Menin-MLL interaction inhibitor, and it proved that introduction of 4-amino pyrrolo[2,3-d]pyrimidine to occupy the P10 hydrophobic pocket was new idea for design of novel Menin-MLL interaction inhibitors.

Antioxidant, Cytotoxic, Anti-Glycation, and Anti-Tyrosinase Compounds from the Leaves of Uvaria Siamensis.

A new oxidized heptene, 7-benzoyloxy-4-hydroxy-1-ethoxy-2E,4Z-heptadiene-1,6-dione, namely siamheptene A (1), together with eight known compounds (2-9), were isolated from the leaves of Uvaria siamensis. Their structures were elucidated by detailed analysis of spectroscopic (IR, 1D and 2D NMR) and mass spectrometric data. Compound 9 is reported for the first time from Uvaria genus. Siamheptene A was evaluated for cytotoxicity against HeLa (cervical cancer cells), A549 (lung cancer cells), and Vero cells using the MTT assay and screened for antibacterial activities. In addition, the isolated compounds (1-7, and 9) were investigated for their antioxidant (DPPH, FRAP and ABTS+ assays), anti-glycation, and anti-tyrosinase properties. Based on our results, compound 1 had mild cytotoxicity against Hela and A549 cancer cell lines, with IC50 ranging from 31.09 to 31.67 µg/mL. Compound 1 also showed antioxidant activities in all tasted assays. However, it showed no detectable activity (>128 µg/mL) against various bacterial strains, and it has no inhibitory effects on tyrosinase enzymes. Among of all tested compounds, chrysin (5), showcased highest anti-glycation and anti-tyrosinase activities. This comprehensive analysis provides highlighting the potential of 1 as a lead compound for further structural modification and development of cytotoxic or antioxidant agents.

Chemical constituents from the roots of Zygostelma benthamii (Apocynaceae) and their anti-proliferative activities.

Phytochemical investigation of the roots of Zygostelma benthamii Baill. (Apocynaceae) led to the isolation of eleven known compounds. The isolated compounds were identified by analysis of physical and spectroscopic data. We report three phenolic compounds (1-3), four triterpenoids (4-7), one coumarin (8), one lignan (9), one pregnane terpenoid (10), and one diterpenoid (11). It is the first time that Zygostelma benthamii is investigated, and this is therefore the first study of the Zygostelma genus. In addition, compound 7 and 11 are reported from the Apocynaceae family for the first time. Compounds 6, 7, 10 and 11 were evaluated against several cancer cell lines (KKU-M213B, KKU-100, KKU-M055, and A549) and Vero cells. Compound 10 showed strong anti-proliferative activity against all the selected cell lines, with IC50 values in the range of 1.70-6.8 µg/mL.

The Bi-(AID-1-T) G-Quadruplex Has a Janus Effect on Primary and Recurrent Gliomas: Anti-Proliferation and Pro-Migration.

High-grade gliomas are considered an incurable disease. Despite all the various therapy options available, patient survival remains low, and the tumor usually returns. Tumor resistance to conventional therapy and stimulation of the migratory activity of surviving cells are the main factors that lead to recurrent tumors. When developing new treatment approaches, the effect is most often evaluated on standard and phenotypically depleted cancer cell lines. Moreover, there is much focus on the anti-proliferative effect of such therapies without considering the possible stimulation of migratory activity. In this paper, we studied how glioma cell migration changes after exposure to bi-(AID-1-T), an anti-proliferative aptamer. We investigated the effect of this aptamer on eight human glioma cell cultures (Grades III and IV) that were derived from patients' tumor tissue; the difference between primary and recurrent tumors was taken into account. Despite its strong anti-proliferative activity, bi-(AID-1-T) was shown to induce migration of recurrent tumor cells. This result shows the importance of studying the effect of therapeutic molecules on the invasive properties of glioma tumor cells in order to reduce the likelihood of inducing tumor recurrence.

Cloning, expression, and characterization of a novel thermo-acidophilic l-asparaginase of Pseudomonas aeruginosa CSPS4.

In the present investigation, a soil isolate Pseudomonas aeruginosa CSPS4 was used for retrieving the l-asparaginase encoding gene (Asn_PA) of size 1089 bp. The gene was successfully cloned into the pET28a (+) vector and expressed into E. coli BL21(DE3) for characterization of the protein. The recombinant rAsn_PA enzyme was purified by affinity chromatography using Ni-NTA2+ resins. Molecular weight analysis using SDS-PAGE unveiled rAsn_PA as a monomeric protein of molecular weight ~ 35 kDa. On characterization, the recombinant rAsn_PA showed optimum pH and temperature of 6.0 and 60 °C, respectively, along with significant stability at 50-70 °C, along with 50% residual activity at 80 °C after 3 h of incubation. Similarly, the rAsn_PA exhibited asparaginase activity over a broad pH range between 4 and 8. The enzyme was not significantly inhibited in the presence of detergents. The rAsn_PA was grouped into the asparaginase-glutaminase family II due to the glutaminase activity. The purified rAsn_PA showed antitumor activity by exhibiting a cytotoxic effect on three different cell lines, where IC50 of purified rAsn_PA was 2.3 IU, 3.7 IU, and 20.5 IU for HL-60, MOLM-13, and K-562 cell lines, respectively. Thus, recombinant rAsn_PA of P. aeruginosa CSPS4 may also be explored as an antitumor agent after reducing or minimizing the glutaminase activity. Thermo-acidophilic properties of rAsn_PA make it a novel enzyme that needs to be further investigated.

Synthesis and Biological Evaluation of 2-Substituted Quinazolin-4(3H)-Ones with Antiproliferative Activities.

Sixteen new 2-substituted quinazolines were synthesized using a straightforward methodology starting from 2-methoxybezoic acid or 3-methoxy-2-naphthoic acid. The anti-proliferative activity of the target compounds was evaluated against nine cancer cell lines. Additionally, all the compounds were screened for their potency and selectivity against a panel of 109 kinases and four bromodomains, using Differential Scanning Fluorimetry (DSF). Compound 17 bearing a 2-methoxyphenyl substitution along with a basic side chain displayed a remarkable profile against the majority of the tested cell lines.

Synthesis, crystal structure and in vitro anti-proliferative activity of 2-[(4-acetyl-phen-yl)carbamo-yl]phenyl acetate.

2-[(4-Acetyl-phen-yl)carbamo-yl]phenyl acetate, C17H15NO4, has been synthesized and structurally characterized. In the structure, N-H⋯O hydrogen-bonding inter-actions form chains of mol-ecules aligned along the [101] direction. The chains are linked by π-π and C-H⋯π inter-actions, forming a three dimensional network. The compound has been screened for in vitro anti-proliferative activity revealing considerable activity.

Anti-microbial and anti-cancer efficacy of acetone extract of Rosa chinensis against resistant strain and lung cancer cell line.

BACKGROUND: Screening of herbal plants for various therapeutic properties is the hour as it shows promising activity. Scientific evidence of the pharmacological activity of the plant strengthens the traditional application of plants. METHODS: Rose flowers (Rosa chinensis) were procured and grounded into a coarse powder. The DNA was isolated from rose flower and molecular identification was performed by rbcL-BF and rbcL-724R primers. Antibacterial activity was evaluated by using disc and agar diffusion methods and the anti-cancer effect of the rose flower extract (RE) was examined using MTT assay in lung cancer cell line. The mechanism of cell death induced by RE was qualitatively measured using Acridine orange/Ethidium bromide staining and Hoechst staining. GC-MS analysis was performed using GC-MS-5975C. RESULT: The RE showed potent antimicrobial activity against various ATCC cultures. The rose extract strongly inhibits the growth of ESBL resistant organism along with inhibition of biofilm formation in the ESBL resistant organism. The extract caused apoptotic and necrotic cell death in lung cancer cells. GC-MS analysis demonstrated the presence of several biologically active compounds such as Clindamycin, Phytol, Octanoic acid, and Stigmasterol which might be the reason for the therapeutic properties of the plant. CONCLUSION: This study shows the antimicrobial and biofilm inhibition activity against the clinical isolates of Klebsiella pneumonia. The study shows the cytotoxic and apoptotic activity in A549 cancer cell line. Thus, the plant may act as a potent antimicrobial drug against resistant strains.