Human Adenocarcinoma Research Articles

GC‐MS Profiling and Therapeutic Potentials of Prosopis juliflora (Sw.) DC: Cytotoxic and Antimicrobial Insights

Plants belonging to the genus Prosopis L. (family Fabaceae, subfamily Mimosoideae) have gained significant popularity in traditional medicine due to their potential as anticancer, antidiabetic, anti‐inflammatory, and antibacterial compounds. The primary objective of this work was to determine the phytochemical composition of the ethanolic extract derived from Prosopis juliflora leaves, as well as to assess its antibacterial and cytotoxic properties. The phytochemical screening using GC‐MS revealed the presence of phytosteroids, ketone, esters, diisooctyl phthalate, and triterpenes. Besides, varying amounts of some silicon derivatives, which were reported to have antimicrobial activity, were detected with octasiloxane, which showed the highest amount (18.47%). 6‐Ethoxy‐6‐methyl‐2‐cyclohexenone (antioxidant, antidiabetic, antiobesity, and antimicrobial) was detected in considerable quantity. Cytotoxic activity was seen in human breast cancer (MCF‐7), human ovary adenocarcinoma (A2780), and human colon adenocarcinoma (HT‐29) cell lines, as well as in normal human fetal lung fibroblasts (MRC‐5), when subjected to the MTT assay. The plant extract exhibited the highest level of activity (5.75 μg/mL) against the A2780 cell line, with the MCF‐7 cell line showing a somewhat lower level of activity (18.49 μg/mL). The antibacterial effect of the plant extracts was evaluated against four standard Gram‐positive and four standard Gram‐negative. The antimicrobial potential was observed only against Staphylococcus aureus which recorded a 14.5 ± 0.05 mm inhibition zone. The present study has demonstrated the identification of bioactive constituents in P. juliflora plant extracts, which exhibit significant cytotoxic activity against breast and colon malignancies. The study also highlighted P. juliflora extract as an antibacterial against S. aureus.

Phytochemical profile by LC-MS/MS analysis and evaluation of antioxidant, antidiabetic, anti-Alzheimer, and anticancer activity of Onobrychis argyrea leaf extracts

IntroductionStudies on different species of Onobrychis, a member of the Fabaceae family, have revealed a number of biological activities with potential applications in alternative medicine. The phytochemical content of the plant Onobrychis argyrea subsp. argyrea and some of the important biological activities linked to its metabolism are quite limited. Therefore, this study was the first to determine the content of secondary metabolites in this species and to elucidate important biological activities related to metabolism. MethodsLC-MS/MS was used for the quantitative analysis of bioactive compounds in the aerial part of O. argyrea extracts. The antioxidant properties of the extracts were assessed based on their ability to scavenge DPPH radicals and reduce iron ions. The anti-diabetic effect of the extracts was tested by the inhibition of α-amylase and α-glycosidase enzymes, and the anti-Alzheimer's ability was tested by the inhibition of the enzymes AChE and BChE. The cytotoxic effects of the extracts were tested on four different cancer lines, namely A-549, HT-29, MCF-7 and MDA-MB 453 using the XTT assay. The mechanism of the anti-cancer effect was determined by means of flow cytometry analysis on HT-29 cells. ResultsTwenty-nine phytochemicals were identified via the LC-MS/MS analysis in the plant extracts. The most abundant phytochemicals in the extracts were quinic acid, isoquercitrin, epicatechin, and routine, respectively. Antioxidant analysis showed that among all extracts, methanol extract (ME) was most effective in scavenging DPPH (IC50: 23.93 ± 0.96 µg/mL) and in reducing iron ions (53.24 ± 2.14 mgTEAC/g). Enzyme activity studies demonstrated that ME is a potent inhibitor of α-glycosidase (IC50: 15.06±0.64 µg/mL), AChE (IC50: 24.75±0.76 µg/mL), and BChE (IC50: 3.36±0.14 µg/mL). XTT assay results disclosed the strongest anti-proliferative activity of ME against the human colorectal adenocarcinoma HT-29 cell line with an IC50 value of 33.35±0.92 µg/mL. Flow cytometry analysis revealed that ME caused mitochondrial membrane damage in HT-29 cells (**p<0.01) and subsequently induced apoptosis (**p<0.01) by activating the caspase pathway (**p<0.001). ConclusionO. argyrea, rich in bioactive compounds, showed remarkable antioxidant, antidiabetic, Alzheimer's, and anticancer properties in vitro, demonstrating that this plant contains secondary metabolites that may be potential drug candidates for the treatment of metabolic diseases.

A bis-quinoline ruthenium(II) arene complex with submicromolar cytotoxicity in castration-resistant prostate cancer cells.

A new Ru(II) arene chlorido organometallic complex [(η6-p-cymene)(L)RuCl]PF6 (named as pCYRuL) using 2-bis(quinolin-2-ylmethylene) hydrazine (L) was developed that exhibits potent anticancer activity against castration-resistant prostate cancer (CRPC) (IC50 = 0.71 μM), and it is 45 times more effective than the standard drug cisplatin (IC50 = 31.3 μM) in a castration-resistant human prostatic adenocarcinoma cell line (PC-3) but non-toxic in normal human kidney cells (HK2) as well as normal breast cells (MCF10A) and found that pCYRuL exerted anticancer activity via apoptosis induction and cell cycle arrest in the G2/M phase of PC-3 cells.

Formulation and Characterization Studies of Paclitaxel Incorporated Kollidon® SR and Chitosan Nanoparticles: An In vitro Evaluation for Potential Use for Colorectal Cancer Treatment

Background: Chemotherapy is regarded as first-line therapy in various cancer types besides surgical procedures. However, lack of cell selectivity and poor drug targeting to the cancer zone of the active agents results in accumulation in normal tissues with considerably high severe side effects. Therefore, novel drug delivery systems are required to enhance cancer treatment. Objective: In this study, Paclitaxel (PTX) incorporated Kollidon® SR (KSR) and Chitosan (CS) based polymeric nanoparticles were prepared for potential use for colorectal cancer treatment. Methods: Polymeric nanoparticles were prepared by spray dying method. Physicochemical characterization studies were performed with particle size (PS), polydispersity index (PDI), zeta potential (ZP), drug loading (DL %), encapsulation efficiency (EE %) and structural evaluations using differential scanning calorimetry (DSC), X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H-NMR) analyses. Cytotoxicity of the nanoparticles was screened on HT-29 (human colorectal adenocarcinoma) and HTC-15 (Dukes' type C, colorectal adenocarcinoma) cell lines with MTT assay. Results: Analysis revealed the successful incorporation of PTX into the polymeric lattices. Particles showed cytotoxic activity on HT-29 and HTC-15 cell lines, depending on the application dose after 48 hours. Nanoparticles also remained stable at 5°C ± 3°C and 25°C ± 2°C (60% ± 5 Relative Humidity (RH)) during the storage period of 6 months. Conclusion: As a result of the study, KSR and CS-based nanoparticles could be regarded as promising nano-carriers for improved therapeutic efficacy of PTX for colorectal cancer treatment.

Diagnostic and prognostic potential of the intra-tumoral microbiota profile in HPV-independent endocervical adenocarcinoma.

Microbial community dynamics have been involved in numerous diseases, including cancer. The diversity of intertumoral microbiota in human papillomavirus independent endocervical adenocarcinoma (HPVI ECA) is not well-characterized. Our objective is to delineate the intratumoral microbiota profile in HPVI ECA and investigate its potential influence on oncogenesis. We analyzed 45 HPVI ECA cases, comprising 36 gastric-type ECA (GEA) and 9 clear cell carcinomas (CCC). We compared the microbial composition within cancerous and adjacent noncancerous tissue samples using 5R-16S ribosomal DNA sequencing. Further, we investigated the correlation between specific microbes and clinical-pathological metrics as well as patient outcomes. Our findings demonstrate notable differences in the microbial spectra between cancerous and adjacent noncancerous tissues. Amongst HPVI ECA subtypes, GEAs exhibit more microbial variations compared to CCCs. Using the Random Forest algorithm, we identified two distinct microbial signatures that could act as predictive biomarkers for HPVI ECA and differentiate between GEA and CCC. Varied microbial abundances was related to clinical characteristics of HPVI ECA patients. In addition, high levels of Micrococcus and low levels of unknown genus75 from the Comamonadaceae family were associated with poorer outcomes in HPVI ECA patients. Similarly, an abundance of Microbacterium correlated with reduced overall survival (OS), and a high presence of Streptococcaceae family microbes was linked to reduced recurrence-free survival (RFS) in GEA patients. Intriguingly, a high abundance of Micrococcus was also associated with a worse OS in GEA patients. The study reveals distinct microbial signatures in HPVI ECA, which have potential as biomarkers for disease prognosis. The correlation between these tumor-associated microbiota features and clinicopathological characteristics underscores the possibility of microbiome-based interventions. Our research provides a foundation for more in-depth studies into the cervical microbiome's role in HPVI ECA.

Оценка эффективности применения активированной глицирризиновой кислоты у пациенток с ВПЧ-ассоциированными поражениями шейки матки с учетом уровня половых стероидных и гонадотропных пептидных гормонов

Background: the persistence of human papillomavirus (HPV) infection with oncogenic protein expression causes changes in the stratified squamous epithelium, which is the immediate cause of cervical cancer manifestation. The use of the activated glycyrrhizic acid (GA) for HPV-associated cervical lesions is pathogenetically justified. During an experimental study on a culture of human cervical adenocarcinoma cells (HeLa line), it was shown that the antiproliferative effect of GA is enhanced by low concentrations of estradiol and weakened by testosterone. Aim: to evaluate the efficacy of the activated GA in female patients with HPV-associated cervical pathology with respect to the level of sex steroid and gonadotropin-releasing hormones Patients and Methods: a prospective study was conducted with the inclusion of 51 female patients with HPV-associated cervical pathology (ASCUS — atypical squamous epithelial cells of undetermined significance, LSIL — low-grade squamous intraepithelial lesion, HSIL— high-grade squamous intraepithelial lesion according to the Bethesda classification) and the absence of clinical and/or laboratory signs of hyperandrogenism. The following studies were performed: clinical examination, colposcopy, microscopic examination, cytology and immunocytochemistry, as well as hormonal status was evaluated. All female patients received Epigen Intim spray 0.1%, 3 times a day, for 30 days from the moment of inclusion in the study. If indicated, cervical conization was also performed. The treatment efficacy was evaluated 90±7 days after the therapy initiation based on the liquid-based HPV-PAP test results with the determination of p16/Ki67 oncogenic protein co-expression in the cervical epithelium. Changes in the colposcopy results were also evaluated. Results: it was found that the level of estradiol in patients with HSIL was lower versus the patients with ASCUS and LSIL (32 [32.0; 36.0] pg/ml versus 40 [34.5; 45.5] and 40 [33.0; 44.0] pg/ml, respectively, but the difference did not reach statistical significance (p=0.453). 90 days after the follow-up start, according to the cytology results of the cervical epithelium, 50 (98.0%) patients showed the absence of cervical intraepithelial lesions and the absence of p16/Ki67 oncogenic protein co-expression, 48 (94.1%) patients showed no high-risk (HR) HPV DNA, whereas HPV-associated colposcopy signs (anogenital warts, chronic cervicitis signs) persisted only in 6 (11.8%) patients. Conclusion: the use of activated GA in female patients of reproductive age with HPV-associated cervical lesions without clinical and/or laboratory signs of hyperandrogenism allowed to achieve high efficiency indicators: 98.5% — according to the cytology results, 83.3% — in reducing the HR-HPV viral load, 85.7% — in terms of p16/Ki67 oncogenic protein co-expression. KEYWORDS: human papillomavirus, squamous intraepithelial lesion of the cervix, oncogenic protein co-expression, sex steroid hormones, activated glycyrrhizic acid FOR CITATION: Mandrykina Zh.A., Dobrokhotova Yu.E., Ibragimova D.M., Kazieva M.D., Filimonova M.S., Shimanovsky N.L., Akhmetgaliev A.R. Assessment of the activated glycyrrhizic acid efficacy in female patients with HPV-associated cervical lesions with respect to the level of sex steroid and gonadotropin-releasing hormones. Russian Journal of Woman and Child Health. 2024;7(2):127–134 (in Russ.). DOI: 10.32364/2618-8430-2024-7-2-7.

Cytomegalovirus Colitis and Colon Adenocarcinoma: A Case of Unusual Co-existence

The possible association of Cytomegalovirus (CMV) with human colorectal adenocarcinomas was first reported in 1978 by Huang and Roche, who detected CMV DNA in 4 of 7 colonic adenocarcinomas by membrane complementary Ribonucleic AcidDeoxyribonucleic Acid (RNA-DNA) hybridisation. CMV earns its name from the characteristic cytomegalic appearance of intranuclear inclusions in infected cells, which include endothelial cells, histiocytes, macrophages, and epithelial cells. The most common site of CMV infection in the gastrointestinal tract is the colon (55%), followed by the sigmoid colon and rectum (35%) and the gastric antrum (25%). Here, a middle-aged female presenting with pain in the lower abdomen, which was insidious in onset and gradually progressive. Ultrasonography revealed a large intestine dilated and filled with multiple air-fluid levels, indicating bowel obstruction. Multidetector Computed Tomography (MDCT) showed circumferential wall thickening involving the distal half of the transverse colon and descending colon. The case was subjected to laparotomy. The resected segment of the colon was sent for histopathological evaluation, and microscopic examination showed adenocarcinoma and many mucosal ulcers, which on keen observation revealed viral inclusions. The diagnosis of colon adenocarcinoma, with a pathological staging of pT2N0Mx with CMV infection, was rendered. CMV infection was confirmed by immunohistochemistry. The patient was on post-surgery chemotherapy and receiving ganciclovir. On follow-up, the patient was recovering fine. Histopathology examination and IHC remain the gold standard in diagnosing CMV, and the concurrent occurrence of colitis and carcinoma should be kept in mind to assist in proper management.

HucMSC-Ex alleviates DSS-induced colitis in mice by decreasing mast cell activation via the IL-33/ST2 axis.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease that poses challenges in terms of treatment. The precise mechanism underlying the role of human umbilical cord mesenchymal stem cell-derived exosome (HucMSC-Ex) in the inflammatory repair process of IBD remains elusive. Mucosal mast cells accumulate within the intestinal tract and exert regulatory functions in IBD, thus presenting a novel target for addressing this intestinal disease. A mouse model of Dextran Sulfate Sodium (DSS)-induced colitis was established and hucMSC-Ex were administered to investigate their impact on the regulation of intestinal mast cells. An in vitro co-culture model using the human clonal colorectal adenocarcinoma cell line (Caco-2) and human mast cell line (LAD2) was also established for further exploration of the effect of hucMSC-Ex. We observed the accumulation of mast cells in the intestines of patients with IBD as well as mice. In colitis mice, there was an upregulation of mast cell-related tryptase, interleukin-33 (IL-33), and suppression of tumorigenicity 2 receptor (ST2 or IL1RL1), and the function of the intestinal mucosal barrier related to intestinal tight junction protein was weakened. HucMSC-Ex treatment significantly reduced mast cell infiltration and intestinal damage. In the co-culture model, a substantial number of mast cells interact with the epithelial barrier, triggering activation of the IL-33/IL1RL1 (ST2) pathway and subsequent release of inflammatory factors and trypsin. This disruption leads to aberrant expression of tight junction proteins, which can be alleviated by supplementation with hucMSC-Ex. Our results suggest that hucMSC-Ex may reduce the release of mast cell mediators via the IL-33/IL1RL1 (ST2) axis, thereby mitigating its detrimental effects on intestinal barrier function.

Red raspberry (Rubus idaeus) preserves intestinal barrier integrity and reduces oxidative stress in Caco-2 cells exposed to a proinflammatory stimulus.

Growing evidence showed the capacity of (poly)phenols to exert a protective role on intestinal health. Nevertheless, the existing findings are still heterogeneous and the underlying mechanisms remain unclear. This study investigated the potential benefits of a red raspberry (Rubus idaeus) powder on the integrity of the intestinal barrier, focusing on its ability to mitigate the effects of tumor necrosis factor-α (TNF-α)-induced intestinal permeability. Human colorectal adenocarcinoma cells (i.e., Caco-2 cells) were used as a model to assess the impact of red raspberry on intestinal permeability, tight junction expression, and oxidative stress. The Caco-2 cells were differentiated into polarized monolayers and treated with interferon-γ (IFN-γ) (10 ng mL-1) for 24 hours, followed by exposure to TNF-α (10 ng mL-1) in the presence or absence of red raspberry extract (1-5 mg mL-1). The integrity of the intestinal monolayer was evaluated using transepithelial electrical resistance (TEER) and fluorescein isothiocyanate-dextran (FITC-D) efflux assay. Markers of intestinal permeability (claudin-1, occludin, and zonula occludens-1 (ZO-1)) and oxidative stress (8-hydroxy-2-deoxyguanosine (8-OHdG) and protein carbonyl) were assessed using ELISA kits. Treatment with red raspberry resulted in a significant counteraction of TEER value loss (41%; p < 0.01) and a notable reduction in the efflux of FITC-D (-2.5 times; p < 0.01). Additionally, red raspberry attenuated the levels of 8-OHdG (-48.8%; p < 0.01), mitigating the detrimental effects induced by TNF-α. Moreover, red raspberry positively influenced the expression of the integral membrane protein claudin-1 (+18%; p < 0.01), an essential component of tight junctions. These findings contribute to the growing understanding of the beneficial effects of red raspberry in the context of the intestinal barrier. The effect of red raspberry against TNF-α-induced intestinal permeability observed in our in vitro model suggests, for the first time, its potential as a dietary strategy to promote gastrointestinal health.

Ovarian Metastasis from Human Papillomavirus-associated Usual-type Endocervical Adenocarcinoma: Clinicopathological Characteristics for Distinguishing from Primary Ovarian Mucinous or Endometrioid Tumor.

Distinguishing ovarian metastasis of usual-type endocervical adenocarcinoma (UEA) from primary ovarian tumors is often challenging because of several overlapping features. This study aimed to investigate the clinicopathological characteristics and outcomes of patients with metastatic ovarian UEA. Clinicopathological information was collected from eight patients with metastatic ovarian UEA. Immunostaining was also performed. Most patients presented with adnexal masses that were suspected to be primary ovarian tumors. All examined cases showed block p16 positivity in paired primary and metastatic tumors. Five patients who completed post-operative chemotherapy or concurrent chemoradiotherapy (CCRT) did not experience recurrence. In contrast, one patient who refused further treatment after the first CCRT cycle experienced ovarian and peritoneal metastases. One patient with isolated ovarian metastasis left untreated and developed peritoneal metastasis during follow-up. Patients with UEA who received proper management for ovarian metastases showed favorable outcomes. Given that ovarian metastatic UEA can mimic primary ovarian borderline tumor or carcinoma of the mucinous or endometrioid type, pathologists should be aware of this unusual but distinctive morphology to avoid misdiagnosis and inappropriate treatment.

STUDIES ON NOVEL METAL COMPLEXES OF COUMARIN SCHIFF BASE: SYNTHESIS, STABILITY CONSTANT, ANTIMICROBIAL AND ANTICANCER ACTIVITY

A facile synthetic protocol was employed to synthesize new coumarin Schiff base (E)-3-(1-((2-hydroxy-5- methylphenyl)imino)ethyl)-2H-chromen-2-one] and their Co and Cu metal complexes. Synthesized molecules were characterized by various spectroscopic methods. The results of antibacterial studies demonstrated that the maximum level of growth inhibition for S. aureus and B. subtilis was shown by compound 5, with inhibition zones of 16±1 mm and 18.5±1.3 mm, respectively, while, Compound 4 exhibited 12.5±0.5 mm and 14±0.25 mm, respectively. Invitro Cytotoxicity of Cu-complex 5 towards human hepatocellular adenocarcinoma cancer cells, at concentrations of 12.5, 25, 50, and 100 g/mL, displayed a reduction in the percentage of cell viability in a dose-dependent manner, with values of 72.45%, 60.12%, 48.69%, and 23.25%, respectively. The results revealed that Compound 5 has the potential to interact with the bacterial membrane surface, leading to the disruption of the same. Additionally, potentiometric analysis was used to estimate the proton-ligand dissociation constant of HL as well as its metal stability constants with Co2+ and Cu2+ .

Computational Insight and Anticancer Effect of Cinnamic Acid-Derivative Amide Compounds

In this research, a meticulous screening process was conducted using four servers: Drug Target Explorer, Swiss Target Predictor, SEA Predictor, and Target Hunter. The primary objective was to identify a series of potential biological targets related to the regulation of cell growth and apoptosis in cancer cells using cinnamic acid derivatives. This study focused on five specific targets, matrix metallopeptidase 9 (MMP9), apoptosis inducing factor (AIF), aldo-keto reductase family 1 member C3 (AKR1C3), aldo-keto reductase family 1 member B10 (AKR1B10), mitogenactivated protein kinase 14 (MAPK14), all of which are well known to play a significant role in cancer cell dynamics. To explore both molecular recognition and molecular dynamics, a series of in silico investigations (docking and molecular dynamics) were carried out using a collection of 14 cinnamic acid derivatives, including cinnamic acid phenethyl ester (CAPE) as a notable reference molecule due to its widely recognized anticancer effects. Furthermore, preliminary in vitro data revealed a potentially promising cytotoxic effect of (E)-N-[(3,4-dichlorophenyl)methyl]- 3-(4-phenoxyphenyl)-2-propenamide (LQM755) on a human gastric adenocarcinoma cell-line (AGS cells), which are characterized by the overexpression of the MMP9 protein. Therefore, the chemical compound LQM755 provides an initial perspective in the field of cancer therapy.

Designing functionalized nanodiamonds with hyaluronic acid-phospholipid conjugates for enhanced cancer cell targeting and fluorescence imaging capabilities.

Nanomedicine aims to develop smart approaches for treating cancer and other diseases to improve patient survival and quality of life. Novel nanoparticles as nanodiamonds (NDs) represent promising candidates to overcome current limitations. In this study, NDs were functionalized with a 200 kDa hyaluronic acid-phospholipid conjugate (HA/DMPE), enhancing the stability of the nanoparticles in water-based solutions and selectivity for cancer cells overexpressing specific HA cluster determinant 44 (CD44) receptors. These nanoparticles were characterized by diffuse reflectance Fourier-transform infrared spectroscopy, Raman spectroscopy, and photoluminescence spectroscopy, confirming the efficacy of the functionalization process. Scanning electron microscopy was employed to evaluate the size distribution of the dry particles, while dynamic light scattering and zeta potential measurements were utilized to evaluate ND behavior in a water-based medium. Furthermore, the ND biocompatibility and uptake mediated by CD44 receptors in three different models of human adenocarcinoma cells were assessed by performing cytofluorimetric assay and confocal microscopy. HA-functionalized nanodiamonds demonstrated the advantage of active targeting in the presence of cancer cells expressing CD44 on the surface, suggesting higher drug delivery to tumors over non-tumor tissues. Even CD44-poorly expressing cancers could be targeted by the NDs, thanks to their good passive diffusion within cancer cells.

Silver(I) complexes containing antifungal azoles: significant improvement of the anti-Candida potential of the azole drug after its coordination to the silver(I) ion.

Inspired by the emergence of resistance to currently available antifungal therapy and by the great potential of metal complexes for the treatment of various diseases, we synthesized three new silver(I) complexes containing clinically used antifungal azoles as ligands, [Ag(ecz)2]SbF6 (1, ecz is econazole), {[Ag(vcz)2]SbF6}n (2, vcz is voriconazole), and [Ag(ctz)2]SbF6 (3, ctz is clotrimazole), and investigated their antimicrobial properties. The synthesized complexes were characterized by mass spectrometry, IR, UV-vis and 1H NMR spectroscopy, cyclic voltammetry, and single-crystal X-ray diffraction analysis. In the mononuclear complexes 1 and 3 with ecz and ctz, respectively, the silver(I) ion has the expected linear geometry, in which the azoles are monodentately coordinated to this metal center through the N3 imidazole nitrogen atom. In contrast, the vcz-containing complex 2 has a polymeric structure in the solid state in which the silver(I) ions are coordinated by four nitrogen atoms in a distorted tetrahedral geometry. DFT calculations were done to predict the most favorable structures of the studied complexes in DMSO solution. All the studied silver(I) complexes have shown excellent antifungal and good to moderate antibacterial activities with minimal inhibitory concentration (MIC) values in the ranges of 0.01-27.1 and 2.61-47.9 μM on the selected panel of fungi and bacteria, respectively. Importantly, the complexes 1-3 have exhibited a significantly improved antifungal activity compared to the free azoles, with the most pronounced effect observed in the case of complex 2 compared to the parent vcz against Candida glabrata with an increase of activity by five orders of magnitude. Moreover, the silver(I)-azole complexes 2 and 3 significantly inhibited the formation of C. albicans hyphae and biofilms at the subinhibitory concentration of 50% MIC. To investigate the impact of the complex 3 more thoroughly on Candida pathogenesis, its effect on the adherence of C. albicans to A549 cells (human adenocarcinoma alveolar basal epithelial cells), as an initial step of the invasion of host cells, was studied.

Sulfated polysaccharides from Caulerpa lentillifera: Optimizing the process of extraction, structural characteristics, antioxidant capabilities, and anti-glycation properties

The polysaccharides found in Caulerpa lentillifera (sea grape algae) are potentially an important bioactive resource. This study makes use of RSM (response surface methodology) to determine the optimal conditions for the extraction of valuable SGP (sea grape polysaccharides). The findings indicated that a water/raw material ratio of 10:1 mL/g, temperature of 90 °C, and extraction time of 45 min would maximize the yield, with experimentation achieving a yield of 21.576 %. After undergoing purification through DEAE-52 cellulose and Sephacryl S-100 column chromatography, three distinct fractions were obtained, namely SGP11, SGP21, and SGP31, each possessing average molecular weights of 38.24 kDa, 30.13 kDa, and 30.65 kDa, respectively. Following characterization, the fractions were shown to comprise glucose, galacturonic acid, xylose, and mannose, while the sulfate content was in the range of 12.2–21.8 %. Using Fourier transform infrared spectroscopy (FT-IR) it was possible to confirm with absolute certainty the sulfate polysaccharide attributes of SGP11, SGP21, and SGP31. NMR (nuclear magnetic resonance) findings made it clear that SGP11 exhibited α-glycosidic configurations, while the configurations of SGP21 and SGP31 were instead β-glycosidic. The in vitro antioxidant assays which were conducted revealed that each of the fractions was able to demonstrate detectable scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical cations. All fractions were also found to exhibit the capacity to scavenge NO radicals in a dose-dependent manner. SGP11, SGP21, and SGP31 were also able to display cellular antioxidant activity (CAA) against the human adenocarcinoma colon (Caco-2) cell line when oxidative damage was induced. The concentration levels were found to govern the extent of such activity. Moreover, purified SGP were found to exert strong inhibitory effects upon glycation, with the responses dependent upon dosage, thus confirming the potential for SGP to find a role as a natural resource for the production of polysaccharide-based antioxidant drugs, or products to promote improved health.

A novel peptide derived from Zingiber cassumunar rhizomes exhibits anticancer activity against the colon adenocarcinoma cells (Caco-2) via the induction of intrinsic apoptosis signaling.

This paper presents the initial exploration of the free radical scavenging capabilities of peptides derived from protein hydrolysates (PPH) obtained from Zingiber cassumunar rhizomes (Phlai). To replicate the conditions of gastrointestinal digestion, a combination of pepsin and pancreatin proteolysis was employed to generate these hydrolysates. Subsequently, the hydrolysate underwent fractionation using molecular weight cut-off membranes at 10, 5, 3, and 0.65 kDa. The fraction with a molecular weight less than 0.65 kDa exhibited the highest levels ABTS, DPPH, FRAP, and NO radical scavenging activity. Following this, RP-HPLC was used to further separate the fraction with a molecular weight less than 0.65 kDa into three sub-fractions. Among these, the F5 sub-fraction displayed the most prominent radical-scavenging properties. De novo peptide sequencing via quadrupole-time-of-flight-electron spin induction-mass spectrometry identified a pair of novel peptides: Asp-Gly-Ile-Phe-Val-Leu-Asn-Tyr (DGIFVLNY or DY-8) and Ile-Pro-Thr-Asp-Glu-Lys (IPTDEK or IK-6). Database analysis confirmed various properties, including biological activity, toxicity, hydrophilicity, solubility, and potential allergy concerns. Furthermore, when tested on the human adenocarcinoma colon (Caco-2) cell line, two synthetic peptides demonstrated cellular antioxidant activity in a concentration-dependent manner. These peptides were also assessed using the FITC Annexin V apoptosis detection kit with PI, confirming the induction of apoptosis. Notably, the DY-8 peptide induced apoptosis, upregulated mRNA levels of caspase-3, -8, and -9, and downregulated Bcl-2, as confirmed by real-time quantitative polymerase chain reaction (RT-qPCR). Western blot analysis indicated increased pro-apoptotic Bax expression and decreased anti-apoptotic Bcl-2 expression in Caco-2 cells exposed to the DY-8 peptide. Molecular docking analysis revealed that the DY-8 peptide exhibited binding affinity with Bcl-2, Bcl-xL, and Mcl-1, suggesting potential utility in combating colon cancer as functional food ingredients.

Dual PI3K/mTOR inhibitor PF-04979064 regulates tumor growth in gastric cancer and enhances drug sensitivity of gastric cancer cells to 5-FU

Gastric cancer (GC) is characterized by high tumor heterogeneity, increased surgical difficulty, and limited chemotherapy efficacy, and it is associated with a poor prognosis. The abnormal proliferation of cells involves abnormal activation of the PI3K/AKT/mTOR signaling pathway. Inhibition of this signaling pathway can inhibit tumor cell proliferation and induce cell apoptosis. This study evaluated the effect of PF-04979064, a dual inhibitor of PI3K and mTOR, on human GC cells. PF-04979064 significantly inhibited the proliferation of human gastric adenocarcinoma AGS cells and the undifferentiated GC cell line HGC-27, promoting cell apoptosis. Combination treatment with PF-04979064 and the GC first-line clinical drug 5-FU showed synergistic effects, and PF-04979064 markedly increased the sensitivity of GC cells to chemotherapy drugs. Western blot results showed that PF-04979064 significantly inhibited the PI3K/AKT/mTOR signaling pathway in GC cells, whereas RNA seq results demonstrated substantial alterations in gene expression profiles upon treatment with PF-04979064. This study provides insight into the effects of PF-04979064, thereby establishing a solid foundation for its potential clinical application in the treatment of GC.

Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation

Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.

The synergistic lipogenesis inhibition and molecular mechanism of polyphenols and polysaccharides from mulberry leaf

The present study investigated the lipogenesis inhibition effect of mulberry leaf polyphenols (MLPP), polysaccharides (MLPS), polyphenols-polysaccharides complex (PPPS, with a total content portion of 1:2), and the mechanism of polyphenols and polysaccharides synergistic interaction. fatty liver human hepatocellular carcinomas (HepG2) and human colorectal adenocarcinoma (Caco-2)/HepG2 cells co-culture model were established to evaluate the lipogenesis inhibition, while real-time quantitative PCR (RT-qPCR) and non-targeted metabolomics were applied for molecular mechanism elucidation. The results demonstrated that the lipid droplet and total glyceride (TG) inhibition effect of PPPS after in vitro digestion and colon fermentation was better than that of MLPP and MLPS groups, indicating synergistic interaction of polyphenols and polysaccharides. Besides, The PPPS achieved synergism regulation on lipid metabolism through 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR)/Acetyl CoA carboxylas (ACC) signaling pathways. In addition, glycerophospholipids, gamma-aminobutyric acid-betaxanthin and luteolin were the key differential metabolites for synergistic lipogenesis in PPPS group. Furthermore, the differential signaling pathways mainly involved mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB), which might be potential targets for the synergistic interaction as verified by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis.

Antioxidant, AChE inhibitory, and anticancer effects of Verbascum thapsus extract.

Verbascum thapsus (VT) is a medicinal plant that is used in folk medicine to treat a variety of ailments. For this study, the biological functions of VT methanol extract were determined in vitro. The plant's methanol extract was created through the maceration process. The phytochemical composition of plant extracts was investigated using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). The antioxidant capacity of the extract was determined using the DPPH (2,2-diphenyl-1-picrylhydrazil) and ABTS (2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) tests and its cytotoxicity was assessed using the MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole)) assay on the Caco-2 (human colorectal adenocarcinoma cells), LNCaP (Lymph Node Carcinoma of the Prostate), and HEK293 cell lines (Human embryonic kidney 293 cells) used to model colon, prostate, and non-cancerous cells. VT extract showed low DPPH and ABTS radical scavenging activities compared to standard antioxidants at 30 mg/ml concentration. In addition, it was determined that VT extract inhibited acetylcholinesterase enzyme.