Search Results (697)

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder with a pressing need for novel therapeutics. However, current medications only offer symptomatic relief, without tackling the underlying pathology. To explore the bioactive potential of marine-derived fungi, this study focused on Aspergillus terreus C23-3, a strain isolated from the coral Pavona cactus in Xuwen County, China, which showed a richer metabolite fingerprint among the three deposited A. terreus strains. AntiSMASH analysis based on complete genome sequencing predicted 68 biosynthetic gene clusters (BGCs) with 7 BGCs synthesizing compounds reported to have anti-AD potential, including benzodiazepines, benzaldehydes, butenolides, and lovastatin. Liquid chromatography coupled with mass spectrometry (LC-MS)-based combinational metabolomic annotation verified most of the compounds predicted by BGCs with the acetylcholinesterase (AChE) inhibitor territrem B from its fermentation extract. Subsequently, molecular docking showed that these compounds, especially aspulvione B1, possessed strong interactions with AD-related targets including AChE, cyclin-dependent kinase 5-p25 complex (CDK5/p25), glycogen synthase kinase-3β (GSK-3β), and monoamine oxidase-B (MAO-B). In conclusion, the genomic–metabolomic analyses and molecular docking indicated that C23-3 is a high-value source strain for anti-AD natural compounds. Full article

Advanced renal cell carcinoma (RCC) has a poor prognosis; this drives the exploration of alternative systemic therapies to identify more effective treatment options. Recent research has revealed that crebanine, an alkaloid derivative of the Stephania genus, induces apoptotic effects in various cancers; however, a thorough investigation of the role of crebanine in RCC has not been conducted thus far. For this study, we evaluated tumor cell viability, clonogenicity, cell-cycle distributions, morphological changes, and cell mortality with the aim of exploring the antitumor effects of crebanine in RCC. Furthermore, we compared gene and protein expressions using RNA sequencing analysis and Western blotting. The findings indicated that crebanine significantly inhibited RCC colonies and caused G1-phase cell-cycle arrest with sub-G1-phase accumulation, thus leading to suppressed cell proliferation and cell death. In addition, Hoechst 33342 staining was used to observe apoptotic cells, which revealed chromatin condensation and a reduction in the nuclear volume associated with apoptosis. Further, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that differentially expressed genes are involved in the initiation of DNA replication, centrosome duplication, chromosome congression, and mitotic processes in the cell cycle along with signaling pathways, such as I-kappaB kinase/NF-kappaB signaling, Hippo signaling, and intrinsic apoptotic pathways. Consistent with GO and KEGG analyses, increased levels of cleaved caspase-3, cleaved caspase-7, and cleaved PARP, and decreased levels of cIAP1, BCL2, survivin, and claspin were observed. Finally, the expressions of G1/S phase transition cyclin D1, cyclin E/CDK2, and cyclin A2/CDK2 complexes were downregulated. Overall, these findings supported the potential of crebanine as an adjuvant therapy in RCC. Full article

Background: TNBC patients respond poorly to chemotherapy, leading to high mortality rates and a worsening prognosis. Here, we investigated the effect of M-I on TNBC tumor growth suppression and its potential mechanisms. Methods: Signaling pathways were analyzed to study the effect of M-I on TNBC cells (human MDA-MB-231 and mouse 4T1). We used orthotopic mouse models to examine the anti-tumor efficacy of M-I. Tumor volume and the status of tumor-associated macrophages (TAMs) were assessed by qRT-PCR or FACS analysis. Results: We found a significant dose- and time-dependent inhibition of TNBC cell proliferation following treatment with M-I. Cell cycle analysis revealed a shortened S phase in M-I-treated cells and downregulation of AURKA, PLK1, CDC25c, CDK1, and cyclinB1. Furthermore, M-I treatment reduced the expression of pSTAT3, cyclinD1, and c-Myc in TNBC cells. To evaluate the anti-tumor efficacy of M-I, we employed orthotopic TNBC mouse models and observed a significant reduction in tumor growth without measurable toxicity. Next, we analyzed RNA from control and M-I-treated tumors to further assess the status of TAMs and observed a significant decrease in M2-like macrophages in the M-I-treated group. Immortalized bone marrow-derived mouse macrophages (iMacs) exposed to conditioned media (CM) of TNBC cells with or without M-I treatment indicated that the M-I treated CM of TNBC cells significantly reduce the M2phenotype in iMacs. Mechanistically, we found that M-I specifically targets the IL-4/MAPK signaling axis to reduce immunosuppressive M2 macrophage polarization. Conclusions: Our study reveals a novel mechanism by which M-I inhibits TNBC cell proliferation by regulating intracellular signaling and altering TAMs in the tumor microenvironment and highlights its potential as a promising candidate for TNBC therapy. Full article

Marine tunicates are a very attractive and abundant source of secondary metabolites with chemical diversity and biological activity. Fractionation and purification of the organic extract of the Red Sea tunicate Didemnum species resulted in the isolation and identification of three new compounds, didemnosides A and B (1 and 2) and 1,1′,3,3′-bisuracil (3), together with thymidine (4), 2′-deoxyuridine (5), homarine (6), and acetamide (7). Planar structures of the compounds were explained through analyses of their 1D (¹H and ¹³C) and 2D (¹H–¹H COSY, HSQC, and HMBC) NMR spectra and high-resolution mass spectral determinations. Compound 1 exhibited the highest growth inhibition toward the MCF-7 cancer cell line with IC₅₀ values of 0.597 μM, while other compounds were inactive (≥50 μM) against this cell line. On the other hand, compounds 1, 2, and 4–7 moderately inhibited SW-1222 and PC-3 cells with IC₅₀ values ranging between 5.25 and 9.36 μM. Molecular docking analyses of the top three active compounds on each tested cell line exposed stable interactions into the active pockets of estrogen receptor alpha (ESR1), human topoisomerase II alpha (TOP2A), and cyclin-dependent kinase 5 (CDK5) which are contemplated as essential targets in cancer treatments. Thus, compound 1 represents a scaffold for the development of more effective anticancer drugs. Full article

The mechanistic target of the Rapamycin complex 1 (mTORC1) signaling pathway plays a pivotal role in regulating crucial life processes, including cell growth and proliferation, by sensing and integrating various signals, such as growth factors, energy status, and amino acids. Our previous studies showed that activation of the mTORC1 signaling pathway enhances silk protein synthesis and silk gland size. Here, the potential of the molecular mechanism mTORC1 to regulate the growth and development of silk gland cells was investigated. Inhibiting mTORC1 with rapamycin decreased proliferation in the Bombyx mori embryonic (BmE) cells and endoreplication in silk gland cells, reducing CyclinB and CyclinE protein levels and DNA content, and arresting the BmE cell cycle at G2/M. Conversely, the overexpression of Ras homolog enriched in brain (Rheb) led to increased proliferation of BmE cells and endoreplication in silk gland cells, as well as a significant elevation in DNA content. This study provides a molecular explanation for the increase in silk protein synthesis and silk gland length through the activation of mTORC1, thereby refining the regulatory network of the silkworm endoreplication and providing new molecular targets for breeding high-yield varieties of Bombyx mori. Full article

Cellular senescence is a complex process that significantly contributes to the pathogenesis of various diseases, including cancer and neurodegenerative disorders. It is characterized by permanent cell cycle arrest and morphological changes, such as cell enlargement and a decrease in lamin B levels. As organisms age, a secretory phenotype known as the senescence-associated secretory phenotype (SASP) develops, which produces pro-inflammatory factors that can impact surrounding tissues and promote disease. This article discusses the molecular mechanisms regulating senescence, notably the p53/p21 and p16INK4a/pRb pathways, which are crucial for inducing cell cycle arrest. While increased activity of cyclin inhibitors like p16 and p21 serves as a protective mechanism against cancer, their prolonged activation can lead to pathological effects. Additionally, the article examines therapies involving senolytics and senomorphics, which aim to eliminate senescent cells. Current research suggests that targeting senescence may represent a promising strategy for treating various diseases, improving health outcomes, and enhancing the overall quality of life as we age. Full article

Background: Lung cancer is the leading cause of cancer-related death in the male sex worldwide. Non-small cell lung cancer (NSCLC) is the most prevalent type, accounting for 80–85% of cases, and lung adenocarcinoma is the most common and lethal NSCLC subtype, being responsible for ca. 50% of deaths. Despite new therapeutic strategies, lung cancer mortality rates remain high, highlighting the need for the development of new drugs. Objectives: We investigated the pharmacological potential of a series of curcumin-like compounds using two lung adenocarcinoma cell lines as models. Methods and Results: Cell viability assay led to the identification of PQM-214 as the hit compound, and other methodologies were employed to investigate the mechanisms underlying its antitumor potential, including cell cycle analysis, mitotic index determination, assessment of clonogenic capacity, senescence-associated β-galactosidase and annexin V assays, quantitative PCR, and Western blot analyses. The mechanism of action of PQM-214 was investigated in A549 cells, revealing that it effectively inhibits cell proliferation by inducing cell cycle arrest, apoptosis, or senescence. Cell cycle key regulators were significantly modulated by PQM-214, with cyclin E2, MYC, and FOXM1 being downregulated, while senescence markers such as cyclin D1, CDKN1A (p21), IL-8, TIMP1, and TIMP2 were upregulated. Moreover, Western blot results revealed upregulation of cyclin D1 and p21 in PQM-214-treated samples, with a downregulation of cyclin B. Conclusions: PQM-214 seems to act on different molecular targets in lung adenocarcinoma cells, inhibiting cell proliferation and inducing apoptosis. Further studies will be conducted to explore whether PQM-214 can also act as a senolytic agent, which would reinforce its anticancer potential. Full article

Given the escalating global temperatures and the consequent exacerbation of heat stress, dietary interventions have emerged as a promising therapeutic strategy. The gastrointestinal tract, being exquisitely sensitive to thermal challenges, revealing the underlying mechanisms of intestinal cell injury under high temperature, is essential for developing strategies to prevent heat stress. Here, we integrated metabolomic and transcriptomic analyses to investigate the metabolic and genetic changes in murine intestinal cells in response to different levels of heat stress. The results identified the PI3k-Akt-FoxO pathway as the major heat stress regulatory pathway Kin MODE-K cells. The possible regulatory mechanism is to reduce the expression of the FoxO gene through the downstream phosphorylation of PI3K under the stimulation of growth factors such as INS, IGF1 and TGF-β. Then, through acetylation modification, it regulates the expression of the Gadd45 gene, promotes the expression of p19 and BNIP3 genes, and inhibits the expression of the ATG8 gene, thus inducing apoptosis to remove cells that cannot be repaired. It also promotes cyclinB, PLK, and Bcl-6 gene expression in cells surrounding apoptotic cells to inhibit apoptosis. It promotes the expression of RAG1/2 to enhance cellular immunity and regulates the G6pc gene to maintain the homeostasis of glycogen metabolism and glucose under heat stress. Our findings provide a basis for the regulation of intestinal cell damage due to heat stress through dietary interventions. Full article

Seliciclib, a cyclin-dependent kinase 5 (CDK5) inhibitor, has demonstrated neuroprotective potential. However, its therapeutic application is limited by poor permeability across the blood–brain barrier (BBB). In this study, polymeric nanoparticles (NPs) modified with a BBB-targeting peptide ligand (His-Ala-Ile-Tyr-Pro-Arg-His) were employed to encapsulate seliciclib. In vitro transport studies showed that the peptide-modified NPs exhibited significantly greater translocation across a bEnd.3 cell monolayer compared to unmodified NPs. Furthermore, in vivo biodistribution analysis revealed that the brain accumulation of peptide-modified NPs was 3.38-fold higher than that of unmodified NPs. Notably, the peptide-conjugated, seliciclib-loaded NPs demonstrated a significant neuroprotective effect against the neurotoxin 1-methyl-4-phenylpyridinium (MPP⁺) in differentiated SH-SY5Y cells. Full article

WEE1 kinase is a crucial cell cycle regulatory protein that controls the timing of mitotic entry. WEE1, via inhibition of Cyclin-dependent Kinase 1 (CDK1) and Cyclin-dependent Kinase 2 (CDK2), governs the G2-M checkpoint by inhibiting entry into mitosis. The state of balance between WEE family kinases and CDC25C phosphatases restricts CDK1/CycB activity. The WEE kinase family consists of WEE1, PKMYT1, and WEE2 (WEE1B). WEE1 and PKMYT1 regulate entry into mitosis during cell cycle progression, whereas WEE2 governs cell cycle progression during meiosis. Recent studies have identified WEE1 as a potential therapeutic target in several cancers, including therapy-resistant triple-negative breast cancer. Adavosertib’s clinical promise was challenged by inter-individual variations in response and side effects. Because of these promising preclinical outcomes, other WEE1 kinase inhibitors (Azenosertib, SC0191, IMP7068, PD0407824, PD0166285, WEE1-IN-5, Zedoresertib, WEE1-IN-8, and ATRN-1051) are being developed, with several currently being evaluated in clinical trials or as an adjuvant to chemotherapies. Preclinical studies show WEE1 inhibitors induce MHC class 1 antigens and STING when given as combination therapies, suggesting potential additional therapeutic opportunities. Reliable predictors of clinical responses based on mechanistic insights remain an important unmet need. Herein, we review the role of WEE1 inhibition therapy in breast cancer. Full article

Background/Objectives: Currently, there is limited knowledge on the molecular mechanisms of the “non-canonical” Hippo signaling pathway in hematopoietic tumor cells. We have shown that targeting the MST1/2 kinases, which are the key molecules in this signaling pathway, may be an effective approach to the treatment of hematologic tumors. Methods: The methods used in this study include cell growth assays, caspase assays, Western blot hybridizations, flow cytometry, and whole-transcriptome analyses. These methods allowed us to better understand the molecular pathways at play. Results: Our results showed that XMU-MP-1, an inhibitor of MST1/2 kinase, specifically reduces the viability of hematopoietic cancer cells but not breast cancer cells. It effectively inhibits the growth of the tumor B- and T-cell lines by blocking cell cycle progression, mainly during the G2/M phase, inducing apoptosis and autophagy. XMU-MP-1 treatment led to increased caspase 3/7 activity and increased levels of the cleaved PARP protein. Levels of the LC3-II protein were also shown to be increased, while the level of p62 decreased. These changes are associated with apoptosis and autophagy, respectively. RNA-seq analysis has demonstrated that XMU-MP-1 suppressed the expression of cell cycle regulators, such as E2F, and cell division cycle genes CDC6,7,20,25,45; cyclins A2,B1,B2, and cyclin-dependent kinases. At the same time, it increased the expression of genes involved in apoptosis, autophagy, and necroptosis. Conclusions: Combinations of growth assays, caspase assays, Western blotting, and RNA-seq have shown that the dramatic reduction in the number of hematopoietic tumor cells after treatment with XMU-MP-1 is due to both cytostatic and cytotoxic effects. The use of MST1/2 kinase inhibitors could be highly promising for complex therapy of hematological tumors. Full article

Glioblastoma Multiforme (GBM) is one of the most common brain tumors and is associated with aggressive tumor characteristics and extremely poor patient survival. The median survival time for GBM patients is around 12–15 months. Temozolomide (TMZ) is a key chemotherapeutic drug used in the treatment of GBM. However, at least 50% of GBM patients do not respond to TMZ, necessitating the identification of novel therapeutic strategies sensitizing patients to TMZ. In this study, we aimed to investigate the effects of two different tumor suppressor microRNAs (miR-329 and miR-449b) on cell proliferation and migration of GBM cells, and their potential for sensitizing GBM cells to TMZ. Our findings show that MiR-329/449b treatments suppressed spheroid formation and migration of GBM (LN229 and U87) cells. When miR treatments were combined with Temozolomide (TMZ), we also observed that they synergistically enhanced the suppressive effects of TMZ and inhibited the activity of clinically significant NF-KB and Src/FAK signaling pathways, making the combination therapy a viable option to treat GBM, with greater impact on patient survival. Full article

Background/Objectives: This study evaluates intratumoral susceptibility signals (ITSS) as imaging markers for glioma grade prediction and their association with molecular and histopathologic features, in the context of the fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5). Methods: We retrospectively analyzed patients with adult diffuse gliomas who underwent pretreatment magnetic resonance imaging. ITSS were semiquantitatively graded by two radiologists: grade 0 (no signal), grade 1 (1–5), grade 2 (6–10), and grade 3 (≥11). Relative cerebral blood volume (rCBV) and tumor volume were also obtained. Histopathologic features included tumor grade, Ki-67, mitotic count, necrosis, microvascular proliferation, and molecular alterations (isocitrate dehydrogenase [IDH], 1p/19q, cyclin-dependent kinase inhibitors 2A and 2B [CDKN2A/B], and p53). Regression models predicted tumor grade (low: 1–2, high: 3–4) using ITSS, tumor volume, and rCBV. ROC curves and diagnostic performance metrics were analyzed. Results: 99 patients were included. ITSS grading correlated with rCBV, tumor volume, mitotic count, Ki-67, and tumor grade (p < 0.001). ITSS grades 0–1 were associated with oligodendrogliomas and astrocytomas (p < 0.001), IDH mutations (p < 0.001), and 1p/19q co-deletions (p = 0.01). ITSS grades 2–3 were linked to glioblastomas (p < 0.001), necrosis (p < 0.001), microvascular proliferation (p < 0.001), and CDKN2A/B homozygous deletions (p = 0.02). Models combining ITSS with rCBV and volume showed AUC of 0.94 and 0.96 (p < 0.001), outperforming univariate models. Conclusions: Semiquantitative ITSS grading correlates with key histopathologic and molecular glioma features. Combined with perfusion and volumetric parameters, ITSS enhance non-invasive glioma grading, in alignment with WHO CNS5. Full article

Background/Objectives: Cellular aging represents a crucial element in the progression of musculoskeletal diseases, contributing to muscle atrophy, functional decline, and alterations in bone turnover, which promote fragility fractures. However, knowledge about expression patterns of factors potentially involved in aging and senescence at the tissue level remains limited. Our pilot study aimed to characterize the expression profile of cell cycle regulators, factors released by aged cells, and sirtuin 1 (SIRT1) in the muscle tissue of 26 elderly patients undergoing hip arthroplasty, including 13 with low-energy fracture and 13 with osteoarthritis (OA). Methods: The mRNA expression levels of cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin-dependent kinase inhibitor 1B (CDKN1B), cyclin-dependent kinase inhibitor 2A (CDKN2A), p53, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-15 (IL-15), chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3), growth differentiation factor 15 (GDF15), and SIRT1 were evaluated in muscle tissue by qRT-PCR. In addition, immunohistochemistry and Western blotting analysis were conducted to measure the protein levels of SIRT1. Results: A marked muscle atrophy was observed in fractured patients compared to the OA group, in association with an up-regulation of cell cycle regulators and factors released by the aged cells. The expression of matrix metallopeptidase 3 (MMP3), plasminogen activator inhibitor 1 (PAI-1), and fas cell surface death receptor (FAS) was also investigated, although no significant differences were observed between the two experimental groups. Notably, SIRT1 expression was significantly higher in OA patients, confirming its role in maintaining muscle health during aging. Conclusions: Further studies will be needed to clarify the role of SIRT1 in the senescence characteristic of age-related musculoskeletal disorders, counteracting the muscle atrophy that predisposes to fragility fractures. Full article

Cervical cancer remains a major threat to women’s health, with advanced cases often exhibiting recurrence and metastasis due to cancer stem cells driving therapy resistance. This study evaluated fenbendazole (FBZ), a repurposed veterinary anthelmintic, for its antitumor activity dual targeting cervical cancer cells (CCCs) and cervical cancer stem cells (CCSCs). CD133⁺CD44⁺ CCSCs were isolated from HeLa and C-33 A cell lines via immunomagnetic sorting and validated for stemness. Cell proliferation, cell cycle and apoptosis, and protein expression were detected by MST assay, flow cytometry, and Western blot analysis, respectively. FBZ dose-dependently inhibited proliferation, induced G2/M arrest, and triggered apoptosis in both CCCs and CCSCs. Mechanistically, FBZ upregulated cyclin B1 and phosphorylation of cdc25C-Ser198, while downregulating Wee1, phosphorylation of CDK1, and phosphorylation of cdc25C-Ser216, collectively enforcing G2/M blockade. In vivo, FBZ (100 mg/kg) significantly suppressed tumor growth in xenograft models without weight loss, contrasting with cisplatin-induced toxicity. Survival analysis revealed 100% survival in FBZ-treated mice versus 40% in cisplatin and 0% in untreated controls. These findings demonstrate FBZ’s unique ability to simultaneously target bulk tumor cells and therapy-resistant CCSCs via cell cycle disruption, supported by its preclinical safety and efficacy, positioning it as a promising therapeutic candidate for cervical cancer. Full article