Search Results (24)

Background/Objectives: Bendamustine (BEN) combined with rituximab (RTX) remains a standard first-line therapy for transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL). Meanwhile, novel targeted therapies such as Bruton tyrosine kinase inhibitors (BTKis) are increasingly used in the treatment of relapsed/refractory (R/R) MCL. We recently reported that a novel oral formulation of BEN exhibits comparable efficacy to the intravenous counterpart. In this study, we investigated the efficacy of oral BEN administered alone or in combination with the oral BCL-2 inhibitor Venetoclax (VEN) and/or the oral BTKi Acalabrutinib (ACAL), against two human MCL cell lines (Jeko-1 and Z-138) representative of the R/R disease subtype. Methods: We performed in vitro analyses using MTS viability and Annexin V/PI apoptosis assays. For the in vivo studies, all treatments were administered via oral gavage in xenograft mouse models. Therapeutic efficacy was evaluated by monitoring tumor growth and survival. Results: BEN induced significant cytotoxicity in both cell lines at low, clinically relevant concentrations. In contrast, VEN demonstrated limited efficacy as monotherapy, with Z-138 showing sensitivity only at high doses. However, combining BEN with VEN with or without ACAL, enhanced apoptosis and cytotoxicity, with more pronounced effects in Z-138. In vivo, oral BEN significantly reduced tumor growth and prolonged survival in both xenograft models. In the Z-138 model, the addition of VEN ± ACAL further improved survival outcomes. Conclusions: Our findings support the efficacy of oral BEN as both a monotherapy and as part of an all-oral treatment regimen for MCL. These results warrant further investigation into the clinical potential of oral BEN, particularly in combination with targeted agents. Full article

Background/Objectives: Ribosomal Protein Lateral Stalk Subunit P2 (RPLP2), an important ribosomal protein, is mainly involved in modulating protein synthesis and plays an essential role in the carcinogenesis of many cancers. However, its precise impact on diffuse large B-cell lymphoma (DLBCL) remains unknown. Methods: This study utilized siRNA to knock down RPLP2, aiming to investigate its role in DLBCL progression. RT-qPCR and immunohistochemistry (IHC) were employed to assess RPLP2 and frataxin (FXN) expression levels in DLBCL. CCK8 and colony formation assays measured cell proliferation inhibition upon RPLP2 deletion, while transwell migration assays analyzed reduced cell motility. Lipid ROS and iron assays quantified ferroptosis markers to elucidate RPLP2’s regulation of FXN-mediated ferroptosis. Xenograft mouse models validated tumor suppression effects in vivo. Results: Here, we reveal that elevated RPLP2 expression is significantly correlated to unfavorable prognosis in DLBCL patients. In addition, we demonstrate that RPLP2 deletion dramatically reduces the cell proliferation and migration of DLBCL. Besides, knockdown of RPLP2 triggers ferroptosis via regulating ferroptosis suppressor FXN activity. Moreover, we discover that Destruxin b could target RPLP2 to suppress the development of DLBCL. Lastly, the combination of Destruxin b with Dox remarkably improves the anti-tumor effect. Conclusions: In general, the present study reveals the oncogenic role of RPLP2 in DLBCL, uncovers an unrecognized regulatory axis of ferroptosis, and identifies a specific inhibitor targeting RPLP2 to restrain DLBCL progression, suggesting that RPLP2 could be a potential target for DLBCL treatment. Full article

Background: Allergic rhinitis (AR) is triggered by immunoglobulin E (IgE)-mediated immune responses to airborne allergens. Recent studies highlight the pivotal role of T follicular helper 2 (Tfh2) cells in IgE production. Interleukin-37 (IL-37) has emerged as an intrinsic modulator of innate immunity and inflammatory processes. We aimed to investigate the regulatory effect of IL-37 on Tfh2 cells in the pathogenesis of AR. Methods: Blood samples were collected from AR patients and controls. The IL-37 levels and the frequency of Tfh2 cells were detected by enzyme-linked immunosorbent assay (ELISA) and flow cytometry, respectively. The isolated Tfh2 cells were cultured or cocultured with naive B cells. The regulatory effects of IL-37 on Tfh2/B cells were assessed using ELISA, quantitative real-time polymerase chain reaction (qRT-PCR). Mouse models of ovalbumin (OVA)-induced AR were established to explore the effect of IL-37 in vivo. Results: IL-37 suppressed the production of IL-4 and IL-21 by Tfh2 cells and downregulated C-X-C chemokine receptor type 5 (CXCR5) and B-cell lymphoma 6 protein (Bcl6) mRNA expression while upregulating B lymphocyte-induced maturation protein 1 (Blimp1) and signal transducers and activators of transduction5 (STAT5) mRNA. IL-37 decreased IgE production by B cells significantly, and the addition of anti-IL-18 receptor α alleviated this effect. In mouse models, IL-37 reduced nasal rubbing, sneezing, eosinophil counts, OVA-specific IgE, and Tfh2 proportions. Conclusions: IL-37 plays a crucial role in modulating Tfh2 cell responses in AR, suggesting a potential therapeutic target for this condition. Full article

Radioresistance remains a major obstacle in cervical cancer treatment, frequently engendering tumor relapse and metastasis. However, the details of its mechanism of action remain largely enigmatic. This study delineates the prospective impacts of short-form human T-cell lymphoma invasion and metastasis 2 (TIAM2S) involving the radiation resistance of cervical cancer. In this study, we established three pairs of radioresistant (RR) cervical cancer cells (HeLa, C33A and CaSki) and their parental wild-type (WT) cells. We revealed a consistent augmentation of TIAM2S, but not long-form human T-cell lymphoma invasion and metastasis 2 (TIAM2L) were displayed in RR cells that underwent a 6 Gy radiation administration. Remarkably, RR cells exhibited decreased radiosensitivity and abridged apoptosis, as estimated through a clonogenic survival curve assay and Annexin V/Propidium Iodide apoptosis assay, respectively. TIAM2S suppression increased radiosensitivity and enhanced cell apoptosis in RR cells, whereas its forced introduction modestly abolished radiosensitivity and diminished WT cell apoptosis. Furthermore, TIAM2S overexpression notably aggravated RR cell migration, whereas its blockage reduced WT cell mobilities, as confirmed by an in vitro time-lapse recording assay. Notably, augmented lung localization was revealed after a tail-vein injection of CaSki-RR cells using the in vivo short-term lung locomotion BALB/c nude mouse model. TIAM2S impediment notably reduced radioresistance-increased lung locomotion. This study provides evidence that TIAM2S may operate as an innovative signature in cervical cancer that is resistant to radiotherapy. It displays multi-faceted roles including radioprotection, restricting apoptosis, promoting cell proliferation, and escalating cell migration/metastasis. Targeting TIAM2S, together with conventional radiotherapy, may be an innovative strategy for intensifying radiosensitivity and protecting against subsequent uncontrolled tumor growth and metastasis in cervical cancer treatment. Full article

Background: Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin’s lymphoma that primarily affects the skin, rich in hyaluronic acid (HA). HA is a component of the extracellular matrix in the dermis and likely affects the development of CTCL, but the mechanism is poorly understood. Here we show that low-molecular-weight HA (LMWHA) possibly exacerbates CTCL, and bexarotene, already used in CTCL treatment, decreases HA production. Methods: We conducted immunohistochemistry, qRT-PCR, immunoblotting, and HA quantification using both mouse and human specimens to evaluate the impact of HA on CTCL. Additionally, we assessed the effect of bexarotene, which is already used for CTCL treatment, on HA metabolism. Results: HA expression was higher in patients’ serum and skin sections than in healthy controls. HA extracted from the skin of mice inoculated with tumors showed an increase in LMWHA. LMWHA increased lymphoma cell proliferation in vitro and accelerated tumor formation in mice in vivo. LMWHA also created a favorable environment for tumor cells by affecting fibroblasts, vascular endothelial cells, and tumor-associated macrophages. Thus, increased levels of HA, mainly LMWHA, exacerbate CTCL progression by affecting tumor cells and their microenvironment. Bexarotene treatment reduced the amount of total HA in murine tumor-inoculated skin, as well as the supernatant of cultured normal human dermal fibroblasts (NHDFs) and HuT78 cells. Detailed in vitro analyses showed that bexarotene treatment decreased HA synthase (HAS)1 and HAS2 expression in NHDFs and HAS1 and HAS3, and CEMIP expression in HuT78 cells. Chromatin immunoprecipitation assays revealed that bexarotene reduced retinoid X receptor-α binding to the HAS1 and HAS2 promoters in NHDFs. Conclusions: Bexarotene potentially exerts its anti-tumor effect by reducing HA levels through decreased expression of HAS. These findings provide new insights into the process of CTCL development and additional insights regarding bexarotene treatment. Full article

Background: Premature ovarian failure (POF) is a common disease among women, which can cause many complications and seriously threaten women’s physical and mental health. Currently, hormone replacement therapy is the primary treatment for premature ovarian failure. However, the side effects are serious and will increase the chance of breast cancer and endometrial cancer. Deer blood hydrolysate (DBH) is the product of enzymatic hydrolysis of deer blood, has antioxidant, anti-ageing, and anti-fatigue effects, and has the potential to improve premature ovarian failure. Methods: In our experiment, a mouse model of premature ovarian failure was established through intraperitoneal injection of 400 mg/kg/d of D-gal for 42 days. At the same time, different doses of DBH were gavaged to observe its ameliorative effect on premature ovarian failure. Results: The experimental findings indicated that DBH could restore the irregular oestrus cycle of POF mice, improve the abnormal amounts in serum hormones follicle-stimulating hormone (FSH), luteinising hormone (LH), progesterone (P) and estradiol (E2), increase the number of primordial follicles and decrease the number of atretic follicles. In addition, DBH also raised the level of superoxide dismutase (SOD) and reduced the level of malondialdehyde (MDA) and reduced the apoptosis of ovarian granulosa cells in mice. The WB assay results showed that gavage of DBH restored the decrease in the indication of nuclear factor erythroid 2-related factor 2 (Nrf2), Heme Oxygenase-1 (Ho-1), and B-cell lymphoma-2 (Bcl-2) proteins and reduced the elevated expression of Kelch-like ECH-associated protein 1 (Keap1), Bcl-2 associated X protein (Bax), and Cysteinyl aspartate specific proteinase-3 (Caspase-3) proteins that were induced by D-gal. Conclusions: To sum up, the present research indicated that DBH can ameliorate D-gal-induced oxidative stress and apoptosis by regulating the Nrf2/HO-1 signalling pathway and the Bcl-2/Bax/caspase-3 apoptosis pathway, which can be used for further development as a nutraceutical product to improve premature ovarian failure. Full article

Gymnema sylvestre (GS) is a perennial woody vine native to tropical Asia, China, the Arabian Peninsula, Africa and Australia. GS has been used as a medicinal plant with potential anti-microbial, anti-inflammatory and anti-oxidant properties. This study was conceptualized to evaluate the cytotoxicity potential of Gymnema sylvestre saponin rich fraction (GSSRF) on breast cancer cell lines (MCF-7 and MDA-MB-468) by SRB assay. The anti-tumor activity of GSSRF was assessed in tumor-bearing Elrich ascites carcinoma (EAC) and Dalton’s lymphoma ascites (DLA) mouse models. The anti-oxidant potential of GSSRF was assessed by DPPH radical scavenging assay. The acute toxicity of GSSRF was carried out according to OECD guideline 425. The yield of GSSRF was around 1.4% and the presence of saponin content in GSSRF was confirmed by qualitative and Fourier transform infrared spectroscopic (FTIR) analysis. The in vitro cytotoxic effects of GSSRF on breast cancer cell lines were promising and found to be dose-dependent. An acute toxicity study of GSSRF was found to be safe at 2000 mg/kg body weight. GSSRF treatment has shown a significant increase in the body weight and the life span of EAC-bearing mice in a dose-dependent manner when compared with the control group. In the solid tumor model, the doses of 100 and 200 mg/kg body weight per day have shown about 46.70% and 60.80% reduction in tumor weight and controlled the tumor weight until the 30th day when compared with the control group. The activity of GSSRF in both models was similar to the cisplatin, a standard anticancer agent used in the study. Together, these results open the door for detailed investigations of anti-tumor potentials of GSSRF in specific tumor models, mechanistic studies and clinical trials leading to promising novel therapeutics for cancer therapy. Full article

Endophytic fungi including black aspergilli have the potential to synthesize multiple bioactive secondary metabolites. Therefore, the search for active metabolites from endophytic fungi against pathogenic microbes has become a necessity for alternative and promising strategies. In this study, 25 endophytic fungal isolates associated with Malus domestica were isolated, grown, and fermented on a solid rice medium. Subsequently, their ethyl acetate crude extracts were pretested for biological activity. One endophytic fungal isolate demonstrated the highest activity and was chosen for further investigation. Based on its phenotypic, ITS ribosomal gene sequences, and phylogenetic characterization, this isolate was identified as Aspergillus tubingensis strain AN103 with the accession number (KR184138). Chemical investigations of its fermented cultures yielded four compounds: Pyranonigrin A (1), Fonsecin (2), TMC 256 A1 (3), and Asperazine (4). Furthermore, ¹H-NMR, HPLC, and LC-MS were performed for the identification and structure elucidation of these metabolites. The isolated pure compounds showed moderate-to-potent antibacterial activities against Pseudomonas aeruginosa and Escherichia coli (MIC value ranged from 31 and 121 to 14.5 and 58.3 μg/mL), respectively; in addition, the time–kill kinetics for the highly sensitive bacteria against isolated compounds was also investigated. The antifungal activity results show that (3) and (4) had the maximum effect against Fusarium solani and A. niger with inhibition zones of 16.40 ± 0.55 and 16.20 ± 0.20 mm, respectively, and (2) had the best effect against Candida albicans, with an inhibition zone of 17.8 ± 1.35 mm. Moreover, in a cytotoxicity assay against mouse lymphoma cell line L5178Y, (4) exhibited moderate cytotoxicity (49% inhibition), whereas (1–3) reported weak cytotoxicity (15, 26, and 19% inhibition), respectively. Our results reveal that these compounds might be useful to develop potential cytotoxic and antimicrobial drugs and an alternative source for various medical and pharmaceutical fields. Full article

Chimeric antigen receptor expression T (CAR-T) cell therapy has been shown be efficacious against relapsed/refractory B-cell malignant lymphoma and has attracted attention as an innovative cancer treatment. However, cells of solid tumors are less accessible to CAR-T cells; moreover, CAR-T function is decreased in the immunosuppressive state of the tumor microenvironment. Since most tumors induce angiogenesis, we constructed CAR-T cells targeting roundabout homolog 4 (Robo4), which is expressed at high levels in tumor vascular endothelial cells, by incorporating three anti-Robo4 single-chain variable fragments (scFv) that were identified using phage display. We found that binding affinities of the three CARs to mouse and human Robo4 reflected their scFv affinities. More importantly, when each CAR-T cell was assayed in vitro, antigen-specific cytotoxicity, cytokine-producing ability, and proliferation were correlated with binding affinity for Robo4. In vivo, all three T-cells inhibited tumor growth in a B16BL6 murine model, which also correlated with Robo4 binding affinities. However, growth inhibition of mouse Robo4-expressing tumors was observed only in the model with CAR-T cells with the lowest Robo4 affinity. Therefore, at high Robo4 expression, CAR-T in vitro and in vivo were no longer correlated, suggesting that clinical tumors will require Robo4 expression assays. Full article

Worldwide antimicrobial resistance is partly caused by the overuse of antibiotics as growth promoters. Based on the known bactericidal effect of silver, a new material containing silver in a clay base was developed to be used as feed additive. An in vitro genotoxicity evaluation of this silver-kaolin clay formulation was conducted, which included the mouse lymphoma assay in L5178Y TK^+/− cells and the micronucleus test in TK6 cells, following the principles of the OECD guidelines 490 and 487, respectively. As a complement, the standard and Fpg-modified comet assays for the evaluation of strand breaks, alkali labile sites and oxidative DNA damage were also performed in TK6 cells. The formulation was tested without metabolic activation after an exposure of 3 h and 24 h; its corresponding release in medium, after the continuous agitation of the silver-kaolin for 24 h was also evaluated. Under the conditions tested, the test compound did not produce gene mutations, chromosomal aberrations or DNA damage (i.e., strand breaks, alkali labile sites or oxidized bases). Considering the results obtained in the present study, the formulation seems to be a promising material to be used as antimicrobial in animal feed. Full article

Dregamine (1), a major monoterpene indole alkaloid isolated from Tabernaemontana elegans, was submitted to chemical transformation of the ketone function, yielding 19 azines (3–21) and 11 semicarbazones (22–32) bearing aliphatic or aromatic substituents. Their structures were assigned mainly by 1D and 2D NMR (COSY, HMQC, and HMBC) experiments. Compounds 3–32 were evaluated as multidrug resistance (MDR) reversers through functional and chemosensitivity assays in a human ABCB1-transfected mouse T-lymphoma cell model, overexpressing P-glycoprotein. A significant increase of P-gp inhibitory activity was observed for most derivatives, mainly those containing azine moieties with aromatic substituents. Compounds with trimethoxyphenyl (17) or naphthyl motifs (18, 19) were among the most active, exhibiting strong inhibition at 0.2 µM. Moreover, most of the derivatives showed selective antiproliferative effects toward resistant cells, having a collateral sensitivity effect. In drug combination assays, all compounds showed to interact synergistically with doxorubicin. Selected compounds (12, 17, 18, 20, and 29) were evaluated in the ATPase activity assay, in which all compounds but 12 behaved as inhibitors. To gather further insights on drug–receptor interactions, in silico studies were also addressed. A QSAR model allowed us to deduce that compounds bearing bulky and lipophilic substituents were stronger P-gp inhibitors. Full article

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-Lepr^db/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria. Full article

Essential oils obtained by hydrodistillation of Montanoa quadrangularis leaves, flowers, and stems were analyzed by GC and GC/MS techniques revealing myrcene, limonene, β-phellandrene, and sabinene among the main components. The aim of the present study was to evaluate the MDR modulator activity on human MDR1 gene transfected mouse lymphoma cell line and the antimicrobial activity on the essential oils obtained from different parts of the species under investigation. The results revealed that MQL caused a similar increase in the fluorescence activity of the cells at 0.02 μL/mL comparing to the Verapamil^® value. The antimicrobial assay was carried out according to the disc diffusion method. Five different bacterial strains (Staphylococcus epidermidis, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli AG 100, and Escherichia coli AG100A) were treated with the essential oils and the zones of inhibition were determined on TSA plates and TSA agar plates supplemented with Tween 20. MQF and MQL showed activity against B. subtilis, S. epidermidis, and E. coli AG 100A while MQS was only active against E. coli AG 100A on TSA agar plates experiment. In case of TSA agar plates supplemented with 0.1 v/v% Tween 20 detergent, MQF showed inhibition on B. subtilis, S. epidermidis, and E. coli AG 100A; MQL was active against B. subtilis, E. coli AG 100, and E. coli AG 100A while MQS was only active against E. coli AG 100A. Full article

Due to their intrinsic viscosity and hydrophilicity, nanohydrogel systems are used to significantly increase the efficiency of commercial contrast agents for MRI and thus effectively improve the sensitivity of the MRI technique. Since chitosan (CS) is a biocompatible polysaccharide frequently used in biomedical applications, we aimed to prepare chitosan nanohydrogels (NGs) by ionic gelation, the polysaccharide being further grafted with rhodamine (RBITC) and fluorescein isothiocyanate (FITC). In this way, the cytotoxic effect of different concentrations (5, 15, 30, 60, and 120 µg/mL) of the fluorescent CS-FITC and CS-RBITC NGs was investigated by assessing the plasma membrane integrity and the metabolic activity of RAW 264.7 murine macrophages and A20 mouse lymphoma B cells following exposure for 6 and 24 h. The cell viability (MTT assay) and lactate dehydrogenase activity were analyzed by spectrophotometric methods, while cellular uptake was observed by fluorescence microscopy. Our results showed that the exposure to CS-FITC and CS-RBITC NGs for 6 and 24 h did not induce significant changes to RAW 264.7 and A20 cells compared to control, proving a good nanogel biocompatibility for both cell lines. In addition, the fluorescence microscopy showed that cellular uptake was quite rapid and efficient for the NGs tested. Taking all of these into consideration, we can conclude that all types of nanohydrogels were biocompatible, being internalized in both cell types with predominantly cytoplasmic localization. Full article

Silver nanoparticles (AgNPs) are widely used in diverse sectors such as medicine, food, cosmetics, household items, textiles and electronics. Given the extent of human exposure to AgNPs, information about the toxicological effects of such products is required to ensure their safety. For this reason, we performed a bibliographic review of the genotoxicity studies carried out with AgNPs over the last six years. A total of 43 articles that used well-established standard assays (i.e., in vitro mouse lymphoma assays, in vitro micronucleus tests, in vitro comet assays, in vivo micronucleus tests, in vivo chromosome aberration tests and in vivo comet assays), were selected. The results showed that AgNPs produce genotoxic effects at all DNA damage levels evaluated, in both in vitro and in vivo assays. However, a higher proportion of positive results was obtained in the in vitro studies. Some authors observed that coating and size had an effect on both in vitro and in vivo results. None of the studies included a complete battery of assays, as recommended by ICH and EFSA guidelines, and few of the authors followed OECD guidelines when performing assays. A complete genotoxicological characterization of AgNPs is required for decision-making. Full article