Multiple myeloma (MM) remains an incurable hematologic malignancy due to the inevitable development of drug resistance, particularly in relapsed or refractory cases. Post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, and glycosylation, play pivotal roles in regulating protein function, stability, and interactions, thereby influencing MM pathogenesis and therapeutic resistance. This review comprehensively explores the mechanisms by which dysregulated PTMs contribute to drug resistance in MM, focusing on their impact on key signaling pathways, metabolic reprogramming, and the tumor microenvironment. We highlight how PTMs modulate drug uptake, alter drug targets, and regulate cell survival signals, ultimately promoting resistance to PIs, IMiDs, and other therapeutic agents. Furthermore, we discuss emerging therapeutic strategies targeting PTM-related pathways, which offer promising avenues for overcoming resistance to treatment. By integrating preclinical and clinical insights, this review underscores the potential of PTM-targeted therapies to enhance treatment efficacy and improve patient outcomes in MM.

The difference in chicken egg production is closely related to the efficiency of follicle selection, which is marked by granulosa cell differentiation and progesterone production with cholesterol as the substrate. The conversion of 7-dehydrocholesterol to cholesterol catalyzed by 7-Dehydrocholesterol reductase (DHCR7) is the rate-limiting step in cholesterol synthesis. Our previous study revealed that estrogen enhanced the mRNA expression of three DHCR7 transcript variants (T1, T3, and T4) in a dose-dependent manner in the granulosa cells of chicken pre-hierarchical follicles (Pre-GCs). This study investigates the molecular mechanisms through which estrogen regulates DHCR7 in chicken Pre-GCs. At the transcriptional level, through CUT&RUN-qPCR, we found that under basal conditions, sterol-regulatory element binding protein 2 (SREBP2) bound to the promoters of three DHCR7 transcript variants to promote cholesterol synthesis in Pre-GCs to maintain low cholesterol levels; meanwhile upon estrogen treatment, estrogen receptors α and β bound to the regulatory regions of three chicken DHCR7 transcript variants, leading to a reduction in the interaction between SREBP2 and DHCR7. At the translational level, the upstream open reading frames (uORFs) and N6-methyladenosine (m6A) modification in the 5'UTR of different DHCR7 transcripts differentially regulate the expression of T3 and T4, as detected by dual-luciferase reporter assays, but this regulation is not affected by estrogen. This study systematically explores the molecular mechanisms through which estrogen upregulates DHCR7 expression in chicken Pre-GCs and provides a clue for understanding the molecular mechanisms underlying cholesterol synthesis in chicken ovarian follicles.

Inhibitors of cytosolic phospholipase A2 (GIVA cPLA2) have received great attention, since this enzyme is involved in a number of inflammatory diseases, including cancer and auto-immune and neurodegenerative diseases. Traditionally, the effects of GIVA cPLA2 inhibitors in cells have been studied by determining the inhibition of arachidonic acid release. However, although to a lesser extent, GIVA cPLA2 may also hydrolyze glycerophospholipids, releasing other free fatty acids (FFAs), such as linoleic acid or oleic acid. In the present work, we applied a liquid chromatography-high-resolution mass spectrometry method to study the levels of intracellular FFAs, after treating cells with selected GIVA cPLA2 inhibitors. Six inhibitors belonging to different chemical classes were studied, using SH-SY5Y neuroblastoma cells as a model. This lipidomic approach revealed that treatment with each inhibitor created a distinct intracellular FFA profile, suggesting not only inhibitory potency against GIVA cPLA2, but also other parameters affecting the outcome. Potent inhibitors were found to reduce not only arachidonic acid, but also other long-chain FAs, such as adrenic or linoleic acid, even medium-chain FAs, such as caproic or caprylic acid, suggesting that GIVA cPLA2 inhibitors may affect FA metabolic pathways in general. The downregulation of intracellular FFAs may have implications in reprogramming FA metabolism in neurodegenerative diseases and cancer.

FAM46C is a tumor suppressor initially identified in multiple myeloma (MM) but increasingly recognized for its role also in other cancers. Despite its significance, studies exploring the therapeutic potential of FAM46C in combination with targeted treatments remain limited. Sphingosine kinases (SphK1 and SphK2) are key regulators of sphingolipid signaling, a pathway essential for maintaining cell structure and function but frequently deregulated in tumors, making them promising targets for cancer therapy. Preliminary work from our laboratory showed that FAM46C expression synergizes with administration of SKI-I, a pan-inhibitor of sphingosine kinases. In this study, we focused specifically on SphK1, the sphingosine kinase predominantly implicated in cancer and investigated the combinatorial effect of forced FAM46C expression and treatment with PF-543, a selective SphK1 inhibitor. We found that FAM46C overexpression enhances, whereas its downregulation reduces, the cytotoxic efficacy of PF-543 in MM cell lines. Using an in vivo xenograft model, we further validated these findings, showing that FAM46C-expressing MM tumors are indeed sensitive to PF-543 while tumors harboring the D90G loss-of-function variant of FAM46C are not. Overall, our results uncover a novel synergistic interaction between FAM46C expression and SphK1 inhibition, highlighting a promising therapeutic strategy for MM treatment.

Cadmium exposure has been linked to elevated cystatin C levels, disruptions in epigenetic patterns, and increased mortality risk. However, the role of epigenetic modifications in the relationship between cadmium and cystatin C remains poorly understood. Furthermore, it is unclear how cystatin C and epigenetic changes influence the connection between cadmium exposure and mortality outcomes. The study explored the associations among blood cadmium levels, serum cystatin C, an epigenetic biomarker (DNA methylation-predicted cystatin C, DNAmCystatinC), and mortality outcomes.

Scutellarin, a natural compound extracted from Scutellaria barbata, has demonstrated antitumor activity in various cancers. However, its role in ovarian cancer has not been fully explored. This study aims to evaluate the therapeutic potential and underlying mechanisms of Scutellarin in ovarian cancer. The effects of Scutellarin on cell proliferation and migration were assessed in ovarian cancer cell lines including SKOV3, A2780, OVCAR3, and OVCAR8. Patient-derived ovarian cancer organoids were used to further validate the in vitro findings. Calcein-AM and PI staining were used to analyze cell viability, and ATP assays were performed to assess organoid activity. Western blot was used to evaluate the regulation of METTL5 protein by Scutellarin. The gene and protein expression levels of METTL5 and their association with ovarian cancer prognosis were assessed using the databases The Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis 2 (GEPIA2), TNMplot, KM-plotter and The Cancer Genome Atlas (TCGA). The functional role of METTL5 was assessed by transwell migration and colony formation assays, and its involvement in Scutellarin's mechanism of action was confirmed by rescue experiments using wound healing and transwell assays. Scutellarin significantly inhibited the proliferation and migration of ovarian cancer cells. In organoid models, Scutellarin markedly reduced organoid growth, induced cell damage, and decreased ATP levels. Compared to normal ovarian tissue, ovarian cancer tissue exhibited elevated RNA and protein expression levels of METTL5. High METTL5 expression was associated with poorer prognosis in ovarian cancer patients and promoted the migration and clonogenicity of ovarian cancer cells. Scutellarin downregulated METTL5 expression, and rescue experiments demonstrated that Scutellarin inhibited ovarian cancer migration by targeting METTL5. Scutellarin demonstrates potent, broad-spectrum anti-tumor activity in ovarian cancer cell lines, potentially mediated through targeting METTL5. These findings suggest a novel and promising therapeutic strategy for ovarian cancer treatment.

Disruptions in the circadian rhythm are linked to various diseases. The clock gene DEC1 is related to the progression and recurrence of various types of cancer; however, its role in colorectal cancer has not been determined. Therefore, we aimed to evaluate the significance of DEC1 expression level in colorectal cancer and its relationship with prognosis.

To test whether biocide exposure in extended-spectrum β-lactamase-producing Klebsiella pneumoniae (ESBL-Kp) isolates is associated with (i) decreased susceptibility to biocides and antibiotics (co-resistance), (ii) emergence of mutations, (iii) changes in expression of efflux pump and porin genes, and iv) fitness cost.

This study aims to evaluate the efficacy of chemotherapy and optimize treatment strategies for patients with advanced ovarian cancer.

Cardiovascular disease remains a leading cause of morbidity and mortality worldwide, frequently arising from platelet hyperactivation and subsequent thrombus formation. Although conventional antiplatelet therapies are available, challenges, such as drug resistance and bleeding complications, require the development of novel agents. In this study, dihydrogeodin (DHG) was isolated from Fennellia flavipes and evaluated using platelets derived from Sprague-Dawley rats. Platelet aggregation induced by collagen, adenosine diphosphate, or thrombin was assessed by light transmission aggregometry; DHG significantly reduced aggregation in a dose-dependent manner. Further assays demonstrated that DHG suppressed intracellular calcium mobilization, adenosine triphosphate release, and integrin αIIbβ3-dependent fibrinogen binding, thereby impairing clot retraction. Western blot analysis revealed that DHG reduced the phosphorylation of mitogen-activated protein kinases (ERK, JNK, p38) and PI3K/Akt, indicating inhibition across multiple platelet-signaling pathways. Additionally, SwissADME-assisted pharmacokinetics predicted favorable properties without violations of the Lipinski (Pfizer) filter, Muegge (Bayer) filter, Ghose filter, Veber filter, and Egan filter, and network pharmacology revealed inhibition of calcium and MAPK pathways. These results highlight the potential of DHG as a novel antiplatelet agent with broad-spectrum activity and promising drug-like characteristics. Further studies are warranted to assess its therapeutic window, safety profile, and potential for synergistic use with existing antiplatelet drugs.

The purpose of this review is to evaluate the role of epigenetic-targeting approaches in the management of neuroendocrine neoplasms (NENs), particularly as a priming strategy for subsequent therapies. We explore the molecular basis of epigenetic modifications in NENs, and we review preclinical and clinical studies on DNA methyltransferase and histone deacetylase (HDAC) inhibitors.

Glioblastoma (GBM) remains almost uniformly fatal, owing in part to therapy-resistant cancer stem-like cells (CSCs) and to temozolomide (TMZ) resistance driven by O6-methylguanine-DNA methyltransferase (MGMT). Differentiation therapy with all-trans retinoic acid (ATRA) has the potential to attenuate stemness and sensitize GBM to TMZ. We therefore asked whether ATRA reduces expression of key CSC markers and MGMT in established GBM lines.

We previously reported that the level of EGFR expression is directly associated with the survival rate of estrogen receptor-positive (ER+) breast cancer patients. Here, we investigated how ER activation by 17β-estradiol (E2), the most potent form of estrogen, affects the expression or activity of EGFR or EGFR-related genes in ER+ breast cancer cells. As expected, E2 enhanced cell proliferation, the induction of S phase, and tumor growth in ER+ breast cancer models. E2 also increased the expression of secretory proteins, including amphiregulin (AREG), angiogenin, artemin, and CXCL16. We focused on AREG, which is a ligand of the epidermal growth factor receptor (EGFR). The levels of AREG expression were positively correlated with ESR1 expression. Our results also showed higher AREG mRNA expression levels in ER+ breast cancer cells than in ER- breast cancer cells. We treated ER+ breast cancer cells with lapatinib to inhibit the AREG/EGFR signaling pathway and then completely inhibited E2-induced cell proliferation and S-phase induction. Similar to the lapatinib treatment, cell proliferation, S-phase induction, cell migration, and tumor growth were suppressed by AREG knockdown. Taken together, we demonstrated that the induction of AREG by E2 contributes to EGFR activation, which then affects cell proliferation and tumor growth. Therefore, we suggest that AREG acts as an intermediary between EGFR and ER and targeting both ERs and EGFRs through combination therapy could prevent tumor progression in EGFR+ ER+ breast cancer patients.

Age-related degenerative changes in intervertebral discs (IVDs) can lead to lower back pain, and even paralysis. This topic is therefore garnering growing attention in an increasingly ageing society. The oxidative stress-induced degenerative process is a major contributor to apoptosis in nucleus pulposus cells. However, the regulatory mechanism of NAD-dependent protein deacetylase Sirtuin-1 (SIRT1) on apoptosis in oxidative stress-induced rat nucleus pulposus cells remains unclear.

Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care.

Endocrine disrupting chemicals (EDCs) are ubiquitous in the environment and have been shown to interfere with the endocrine system, leading to adverse effects on reproductive health. In females, EDC exposure has been linked to menstrual irregularities, infertility, and pregnancy complications. Epigenetic regulation, which involves modifications to DNA and histones that do not alter the underlying genetic code, plays a crucial role in female reproduction. EDCs have been shown to disrupt epigenetic mechanisms, leading to changes in gene expression that can have long-term effects on reproductive outcomes. Several EDCs, including bisphenol A (BPA) and phthalates, dioxins, and polychlorinated biphenyls (PCBs), have been shown to alter DNA methylation patterns and histone modifications in female reproductive tissues. These changes can lead to altered expression of genes involved in ovarian function, implantation, and placental development. Here, we integrate epidemiological and experimental evidence from the last 20 years to profile the types of diseases that EDCs trigger in the female reproductive system in relation to the uterus, and the corresponding molecular mechanisms that have been studied. In addition, this review will outline the state of knowledge of EDC epigenetic regulation in the uterus and how it impacts reproductive health, as well as identify areas for future research.

Triple negative breast cancer, an inherently aggressive disease, is further impaired by the limited therapeutic options and chemotherapy-resistance; hence, elucidating the signaling nodes underlying chemotherapy resistance is of major interest. Focusing on the differentially expressed genes in recurrent TNBC, we identified TRIM29, a ubiquitin ligase belonging to TRIM family, as a uniquely enriched protein in chemoresistant TNBC. Here, we demonstrate that chemoresistant TNBC cells are inherently aggressive, exhibiting elevated growth and migration potential compared to chemosensitive cells, and in particular, they possess higher TRIM29 expression whose expression level modulation results in altered chemosensitivity. TRIM29 overexpression reduces chemotherapy response whereas TRIM29 knockout not only increases chemosensitivity but also reduces TNBC tumor growth. Tumor-dissociated cells maintain TRIM29 knockout status as well as exhibit similar functional alterations as chemoresistant TNBC cells. Mechanistically, RNA-sequencing of parental-chemosensitive, chemoresistant-inherently overexpressing TRIM29 and chemoresistant-TRIM29 knockout TNBC cells reveals a unique set of genes (S100P, SERPINB3, SERPINB4, CEACAM5, CEACAM6 and CDH6) showing significant upregulation with the acquisition of chemoresistance and downregulation with the TRIM29 knockout. Furthermore, an enrichment of β-catenin pathway in chemoresistant TNBC cells is observed. We uncovered a functional network where S100P, a metastasis inducing secretory factor, bidirectionally interacts with TRIM29, and modulates the expression of SERPINB3, SERPINB4, CEACAM5, CEACAM6 as well as β-catenin pathway genes. Showing the functional importance, S100P inhibitor reduces the growth and mammosphere formation in chemoresistant TNBC. Moreover, combining β-catenin inhibitor with chemotherapy shows synergistic inhibition of chemoresistant TNBC cells. Indeed, higher expression of TRIM29, S100P and β-catenin associates with reduced recurrence free survival. This work proposes TRIM29 as an important node that modulates a unique gene network in chemoresistant TNBC and whose biological impact is mediated by modulation of S100P and β-catenin.

Brassinosteroids (BRs) are known to regulate fruit development, ripening, and metabolic processes in plants. In this study, the impact of exogenous 24-epibrassinolide (EBR) on tomato fruit quality was examined using 'Micro-Tom' tomatoes.

Temozolomide (TMZ) resistance is one of the critical factors contributing to the poor prognosis of glioblastoma (GBM). As a first-line chemotherapeutic agent for GBM, TMZ exerts its cytotoxic effects through DNA alkylation. However, its therapeutic efficacy is significantly compromised by enhanced DNA damage repair (DDR) mechanisms in GBM cells. Although several DDR-targeting drugs have been developed, their clinical outcomes remain suboptimal. Post-translational modifications (PTMs) in GBM cells play a pivotal role in maintaining the genomic stability of DDR mechanisms, including methylguanine-DNA methyltransferase-mediated repair, DNA mismatch repair dysfunction, base excision repair, and double-strand break repair. This review focuses on elucidating the regulatory roles of PTMs in the intrinsic mechanisms underlying TMZ resistance in GBM. Furthermore, we explore the feasibility of enhancing TMZ-induced cytotoxicity by targeting PTM-related enzymatic to disrupt key steps in PTM-mediated DDR pathways. By integrating current preclinical insights and clinical challenges, this work highlights the potential of modulating PTM-driven networks as a novel therapeutic strategy to overcome TMZ resistance and improve treatment outcomes for GBM patients.

Chronic kidney disease (CKD) is a global health challenge marked by progressive renal decline and increased mortality. The interplay between CKD and hypothyroidism, particularly nonthyroidal low-triiodothyronine (T3) syndrome, exacerbates disease progression, driven by HPT axis dysfunction and reduced Klotho levels due to the Wnt/β-catenin pathway activation. This study explored Klotho as a link between CKD and hypothyroidism using an adenine-induced CKD aged mouse model. Exogenous T3 and baicalein (BAI), targeting the Wnt pathway, were used to upregulate Klotho expression. Combined T3 and BAI treatment significantly increased Klotho levels, surpassing individual effects, and suppressed key signaling molecules (TGF, NFκB, GSK3), mitigating renal fibrosis and CKD complications, including cardiovascular disorders and dyslipidemia. This bidirectional approach, enhancing Klotho via T3 and sustained Wnt pathway inhibition, offers a novel and effective strategy for CKD management, particularly in elderly patients with hypothyroidism.