Search Results (283)

Introduction: Glioblastoma (GBM) is the most common and aggressive type of glioma. Although current treatment strategies are well-established, their effectiveness remains limited. Recent studies have highlighted the potential of short-chain fatty acids (SCFAs)—such as acetate, butyrate, propionate, and valeric acid—as therapeutic agents against various solid tumors. Methodology: We evaluated the cell viability of A172, a GBM cell line, upon treatment with SCFAs using MTT assay. We then investigated the underlying molecular mechanisms of cell death induced by sodium butyrate and valeric acid, using their respective IC50 concentrations via Real-Time qPCR. Results: The IC50 values indicated that A172 cells were more sensitive to sodium butyrate and valeric acid (IC50 = 9.22 mM and 19.04 mM, respectively) than to sodium propionate and sodium acetate (IC50 = 41.21 mM and 121.2 mM, respectively) after 72 h of treatment. In cells treated with sodium butyrate, we observed an increased expression of BAK and decreased expression of P53 and CASP1. Treatment with valeric acid led to upregulation of BCL-2, BAK, and RIPK3, along with downregulation of P53. Conclusions: Our preliminary findings suggest that SCFAs, particularly sodium butyrate and valeric acid, can induce cell death in GBM cells through distinct molecular pathways. While further studies are necessary to elucidate the exact mechanisms, these results support the potential of SCFAs as therapeutic candidates for glioblastoma. Full article

Eucalyptus is a highly diverse genus of the Myrtaceae family that is planted worldwide. Many changes occur during callus development, an important process during in vitro plant regeneration. In this study, we conducted methylome and transcriptome analyses to reveal such changes. The results showed that differentially expressed genes between E. camaldulensis (voucher ID: c0009; high embryogenic potential) and E. grandis × urophylla (voucher ID: j0017; low embryogenic potential) during callus development were enriched in plant hormone signal transduction and MAPK (Mitogen-activated protein kinase) signaling pathways. qRT-PCR analysis showed AHP, BAK1, BSK, CRE1, GID1, MKS1, PR-1, PYL, RbohD, and TCH4 could be involved in the callus development and plantlet regeneration capacity. The differences observed in regenerative potential during callus maturation between the two species under study provide a reliable molecular basis for the study of Eucalyptus regeneration mechanisms. Full article

Triple-negative breast cancer (TNBC) represents significant therapeutic challenges due to its aggressive behavior, metabolic plasticity, and lack of targeted treatments, prompting investigation of biologically active triterpene glycosides from the starfish Solaster pacificus. This study evaluated the ability of pacificusoside D (SpD) to synergistically enhance the anticancer efficacy of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) in TNBC MDA-MB-231 cells by targeting mitochondrial oxidative phosphorylation (OXPHOS). Methods included metabolic profiling via glucose uptake, lactate, and glutamate Glo assays; IC₅₀ determination by MTS and trypan blue assays; colony formation evaluation using a soft agar assay; and molecular mechanism elucidation by Western blot, fluorescence microscopy and spectrometry, and flow cytometry analyses. Results demonstrated that MDA-MB-231 cells predominantly utilized glycolysis under basal conditions, shifting to OXPHOS with 2-DG (0.5 mM). IC₅₀ values were 8.0/8.4 mM for 2-DG and 0.3/0.25 μM for SpD after 24 h of cell treatment. SpD exhibited a significant decrease in the number of colonies in MDA-MB-231 cells and possessed synergistic anticancer effects with 2-DG. Mechanistically, SpD increased tumor suppressor VHL expression level, down-regulated expression level of electron transport chain enzymes, generated reactive oxygen species, induced mitochondrial dysfunction, and triggered Bax/Bak-mediated apoptosis. These findings highlighted the synergistic anticancer potential of SpD in combination with 2-DG in aggressive breast cancer, offering insights into improved clinical outcomes in the future. Full article

Increasing evidence implicates mitochondrial/cellular dynamics in ischemia reperfusion (I/R)-induced acute kidney injury (AKI). Sodium-glucose-co-transporter-2 inhibitors (SGLT2is, e.g., canagliflozin, CG) have been shown to mitigate I/R-induced AKI. Here, we hypothesized that CG-improved AKI was associated with altered mitochondrial dynamics and apoptosis in a previously established swine model. CG (300 mg, PO) significantly increased pro-apoptotic genes Bid, Bad, Bax, Bak1 and Casp1 expression (all p < 0.05). Pink1 (p = 0.0019), Optn (p = 0.038), and Map1lc3 (p = 0.0093) expression also increased with CG, implicating mitophagy; PINK1 protein levels were unchanged. The expression of mitochondrial fission regulator Fis1 increased with CG treatment (p = 0.0015) while fusion regulator Opa1 expression decreased (p = 0.038). TUNEL staining showed increased apoptosis primarily in damaged proximal tubular cells of CG animals. Ki67 staining revealed I/R-injury increased cell proliferation throughout the kidney, which was significantly attenuated with CG. Moreover, correlative analysis revealed that AKI severity positively correlated with cell proliferation. In this large animal model, CG reduced AKI via increased mitochondrial fission and pro-apoptotic gene expression, potentiating clearance of damaged mitochondria, and decreased cell proliferation. Future studies should evaluate other SGLT2is as a potential therapeutic for I/R AKI. Full article

Background: Glaucoma is a neurodegenerative disease and the second leading cause of irreversible blindness in developed countries. It is characterized by progressive loss of retinal ganglion cells (RGCs) and optic nerve axons, leading to permanent vision impairment. Although elevated intraocular pressure (IOP) is the main recognized risk factor, recent evidence suggests that ocular and gut microbiota may play a significant role in the onset and progression of glaucoma. Objectives: This study aimed to characterize ocular and gut microbiota alterations in patients with different types of glaucoma. Methods: Five searches were conducted between June and September 2025 using selected keywords. A total of 121 articles were identified, of which 14 met the inclusion criteria following the PRISMA 2020 guidelines. Results: Findings indicate a Mendelian genetic predisposition influencing microbiota composition associated with glaucoma development. Patients treated with benzalkonium chloride (BAK) showed increased Gram-negative and Alphaproteobacteria on the ocular surface, along with enhanced lipopolysaccharide synthesis. Compared with controls, glaucoma patients exhibited reduced Corynebacterium mastiditis and Actinobacteria and increased Firmicutes, Proteobacteria, and Verrucomicrobiota. Dysbiosis was more pronounced in patients with concurrent dry eye disease, characterized by higher Gram-negative taxa and pro-inflammatory microbial activity. Conclusions: Significant differences in ocular and gut microbiota were observed between glaucoma patients and controls, as well as among glaucoma subtypes such as pseudoexfoliation and primary open-angle glaucoma. Age-related dysbiosis and epigenetic factors appear to contribute to disease development. Microbiota profiling may offer new opportunities for improved prediction, management, and treatment of glaucoma. Full article

The incidence and mortality of hepatocellular carcinoma (HCC) are increasing worldwide, underscoring the need for novel therapeutic strategies. Synthetic 2-naphthyl 2-butanamido-2-deoxy-1-thio-β-d-glucopyranoside (612) is a selective inhibitor of β1,4-galactosyltransferase 1 (β4GalT1). In this study, we investigated the cytotoxic effects of 612 across multiple cancer cell lines, with a focus on HCC, and explored the underlying mechanisms. We demonstrate that 612 preferentially exhibits cytotoxicity toward cancer cells with elevated expression of β4GalT family members, while human umbilical vein endothelial cells and immortalized human embryonic kidney epithelial cells are comparatively less sensitive. Treatment with 612 suppresses cancer cell migration and invasion and induces pronounced endoplasmic reticulum and Golgi stress, accompanied by G2/M cell cycle arrest. Furthermore, 612 activates apoptosis through ER stress–associated pathways by downregulating the anti-apoptotic protein Bcl-2 and upregulating pro-apoptotic proteins Bax and Bak, along with activation of caspase-3, -8, and -9. Collectively, these findings identify 612 as a promising anti-cancer candidate targeting β4GalTs-overexpressing HCC cells and warrant further therapeutic development. Full article

The removal of protein-bound uremic toxins (PBUTs) from the blood of kidney failure patients with conventional dialysis is limited. However, as their harmful effects and association with morbidity and mortality in dialysis patients are increasingly recognized, PBUTs have become important therapeutic targets. In this review, PBUT removal with current state-of-the-art dialysis technologies and future perspectives are discussed. Strategies to enhance PBUT clearance include methods that interfere with PBUT–albumin binding, such as chemical displacers, high ionic strength, pH changes, or electromagnetic fields, thereby increasing the free fraction available for dialysis. While these methods have shown promise in vitro, and some also in vivo, long-term safety data are lacking. PBUT removal can also be increased by adsorption, either directly via hemoperfusion, or indirectly, e.g., via sorbents incorporated in a mixed-matrix membrane or dissolved in the dialysate. In the kidney, PBUTs are secreted in the proximal tubules; hence, a cell-based bioartificial kidney (BAK) that secretes PBUTs is proposed as an add-on to current dialysis. Yet both PBUT adsorption strategies and, in particular, BAKs face considerable challenges in upscaling and mass production at acceptable costs. In conclusion, many novel technologies are under development, all requiring further (pre)clinical testing and upscaling before these strategies can be applied in the clinic. Full article

Background and Objectives: This study evaluates the safety, tolerability, and efficacy of preservative-free Dorzolamide 2%-Timolol 0.5% (PF-DT), with a focus on improving the ocular microenvironment in a real-world transition setting. Materials and Methods: A prospective, multicenter, open-label study involving thirty patients with dry eye disease previously treated with BAK-DT was conducted. Participants were transitioned to PF-DT, and evaluated at weeks 4, 12, and 24. The primary endpoint was the Ocular Surface Disease Index (OSDI) score. Secondary outcomes included Break-Up Time (BUT), Schirmer test results, corneal staining, conjunctival hyperemia, intraocular pressure (IOP), and patient satisfaction. Results: Twenty-five patients completed the study. The OSDI improved from 21.5 to 12.5 (p < 0.001), with 60.0% of patients showing improvement and 52.0% achieving complete symptom resolution. Among eyes with corneal staining, 78.4% demonstrated a reduction of at least one grade, and 50.0% of those with conjunctival redness showed similar improvement. By week 24, 78.0% exhibited no corneal staining, and 50.0% had no conjunctival redness. BUT increased from 5.0 to 7.0 (p < 0.01), while IOP decreased by 1 mmHg (p < 0.01). Satisfaction regarding comfort (≥80%) and handling (≥50%) was high, with 88.0% preferring PF-DT. Conclusions: Transitioning to PF-DT improved ocular surface health while maintaining IOP control, supporting the benefits of preservative-free formulations in restoring microenvironment homeostasis and enhancing tolerability and patient satisfaction. Full article

Bakuchiol (BAK), a natural meroterpenoid with antioxidant, anti-inflammatory and anticancer properties, has recently gained attention as a potential adjunct in breast cancer therapy. This review contextualizes breast cancer as a major global health challenge and highlights BAK as a bioactive compound capable of modulating pathways relevant to tumor development and progression. A structured literature search identified studies examining its molecular activity, pharmacological profile, and effects on breast cancer cells and stem cells. Results show that BAK influences oxidative stress regulation, mitochondrial function, apoptosis and estrogen receptor signaling while also affecting PI3K/AKT, MAPK, NF-κB, and EMT-related pathways. In breast cancer models, BAK acts as a selective phytoestrogen, induces S-phase arrest, activates the ATM/ATR–Chk1/Chk2 axis, and triggers mitochondrial apoptosis, particularly in ERα-positive cells. It also suppresses breast cancer stem-cell renewal, promotes BNIP3- and DAPK2-mediated apoptosis, reduces metabolic and transcriptional drivers of metastasis, and shows enhanced anticancer activity in derivative forms. These findings suggest that BAK may provide therapeutic benefit across several mechanisms central to breast cancer biology. In this review, the inclusion criteria encompassed publications describing the action of bakuchiol, its chemical and pharmacological properties, as well as its role in the treatment of various conditions, including cancers. Exclusion criteria included works not related to BAK or its therapeutic use in breast cancer, as well as publications that did not meet basic scientific standards, such as lacking methodological rigor or presenting a low level of scientific evidence. However, current evidence is predominantly in vitro, and limitations such as poor bioavailability and lack of clinical validation underscore the need for further in vivo and translational studies before therapeutic application can be established. Full article

Acute myocardial infarction (AMI) is a significant factor leading to the death of patients with coronary heart disease. Both AMI and reperfusion therapy after AMI cause myocardial cell death, which plays a significant role in heart failure. Following the restoration of blood flow during reperfusion, myocardial cells generate a large amount of oxygen free radicals, causing various forms of myocardial ischemia–reperfusion (IR) injury (IRI), ultimately leading to multiple types of myocardial cell death, among which apoptosis and necroptosis are the two major types. Given the extremely limited regenerative capacity of myocardium, inhibiting myocardial cell apoptosis and necroptosis is a key strategy for reducing mortality in patients with AMI. Both apoptosis and necroptosis are regulated by the BCL2 family of proteins, which were modulated by multiple signaling pathways, converging at BAK/BAX-mediated mitochondrial outer membrane permeabilization (MOMP), as well as mitochondrial inner membrane permeabilization (MIMP). BAK/BAX double knock out (DKO) mice showed reduced cell apoptosis, necroptosis, and infarct size in AMI animal models compared to wild type. This review describes the role of BCL2 family proteins in regulating apoptotic and necroptotic myocardial cell death during AMI and IR, explores the upstream pathways modulating apoptosis and necroptosis, and summarizes the recent advances in targeting BAK and/or BAX for cardiac protection. In addition, targeted delivery of BAK/BAX inhibitors to cardiomyocytes during AMI or myocardial IR has the potential to reduce myocardial cell death and therefore lower the mortality and enhance long-term prognosis for myocardial infarction patients. Full article

The present article reinterprets the history of polyglot lexicography and encyclopedic language projects in late imperial China from the Yuan and the Ming through the Qing periods by tracing a three-stage transformation. The Yuan period inaugurated a foundational regime of phonetic transcription anchored in the ’Phags-pa script (Ch. Basiba zi 八思巴字) while already experimenting with semantic pairing in the early Sino–Mongol glossary conventionally known as Zhiyuan yiyu (至元譯語). The Ming consolidated that legacy into a state curriculum centered on the Huayi yiyu (華夷譯語) corpus, together with frontier manuals such as Beilu yiyu (北虜譯語), which systematized domain-based vocabulary and coupled it with documentary templates for tribute, diplomacy, and administration. The Qing, finally, reconceived multilingual lexicography as a project of imperial integration, recentering Manchu as the pivot language in the Qing wen jian (清文鑒) series and culminating in the five-language Wuti Qing wen jian (五體清文鑒). Specialized compendia such as Xiyu tongwen zhi (西域同文志) normalized toponyms across scripts in newly incorporated territories. Complementing official compilations, market-facing handbooks—including Menggu zazi (蒙古雜字)—and the dialogic textbooks Nogeoldae (Ch. Lao qida 老乞大) and Bak Tongsa (Ch. Piao tongshi 朴通事) produced within Joseon’s translator-training institutions reveal a multi-sited ecosystem in which court, frontier, marketplace, and foreign language schools co-produced the infrastructure of interlingual governance. By following the shift from “how to read” (phonetic) to “what it means” (semantic) and ultimately to “what it governs” (administrative integration), this article argues that polyglot lexicons were not merely repositories of words but instruments that made a multilingual empire legible, speakable, and governable. Full article

Background: Dihydroflavonol 4-reductase (DFR) is pivotal for anthocyanin biosynthesis and plays a crucial role in plant development and stress adaptation. However, a systematic characterization of the DFR gene family is lacking in Lonicera japonica Thunb. Methods: In the present study, based on genome and transcriptome data of L. japonica, the research identified six LjDFR gene family members throughout the entire genome. Results: The LjDFR genes were located on Chr.04 and Chr.09 and the full-length coding sequences of LjDFR1-LjDFR6 were cloned. Subcellular localization analysis showed that LjDFRs are primarily found at the cell membrane and in the nucleus. Phylogenetic analysis showed closer clustering of LjDFR genes with Capsicum annuum and Camellia sinensis. Promoter analysis linked LjDFR genes to light response, hormone signaling, and stress-responses. qRT-PCR analysis demonstrated tissue-specific and stage-specific expression patterns among LjDFR members. Notably, LjDFR2 expression was significantly higher in the intensely pigmented tissues of Lonicera japonica Thunb. var. chinensis (Wats.) Bak. compared to L. japonica. Coupled with its phylogenetic proximity to the anthocyanin-related CsDFRa and CaDFR5 genes, this suggests that LjDFR2 may be positively correlated with anthocyanin accumulation. Additionally, the expression of LjDFR2 and LjDFR4 was markedly induced by both drought and salt stress, indicating their roles in abiotic stress responses. Conclusions: This research provides a foundation for further functional studies of LjDFR genes in anthocyanin biosynthesis and stress resistance and offers candidate genes for molecular breeding of L. japonica. Full article

Here, we show that the aureolic acid-class antibiotic, olivomycin A, exerts potent anticancer activity in renal cell carcinoma (RCC) by disrupting both cell survival and metastatic programs. In A-498 (wild-type p53) and 786-O (loss-of-function in p53 and PTEN) cells, olivomycin A markedly inhibited migratory capacity and reversed epithelial–mesenchymal transition (EMT), as shown by downregulation of nuclear Snail and the mesenchymal marker N-cadherin and restoration of the epithelial markers, E-cadherin and ZO-1. In parallel, olivomycin A induced apoptosis through distinct p53-dependent mechanisms: In A-498 cells, apoptosis was primarily mediated through the intrinsic pathway, characterized by the upregulation of Puma, Bak, and activation of caspase-9. In 786-O cells, caspase-8 activation and Bid truncation were observed alongside mitochondrial involvement, suggesting possible cross-talk apoptotic cascades. Notably, in p53-mutant 786-O cells, treatment with olivomycin A elicited severe genotoxic stress accompanied by robust DNA damage signaling, excessive reactive oxygen species (ROS) accumulation, and lysosomal activation, culminating in extensive mitochondrial removal. Such changes were weaker in p53-wild-type A-498 cells, suggesting that the altered p53 context sensitizes RCC cells to olivomycin A-mediated mitochondrial quality control mechanisms. Collectively, our findings delineate a multifaceted mechanism whereby olivomycin A coordinates EMT suppression, apoptotic induction, and mitochondrial clearance. Thus, olivomycin A has potential as a therapeutic candidate that can target both survival and metastatic pathways in heterogeneous genetic backgrounds. Full article

Parthanatos represents an alternative form of regulated cell death (RCD) mediated by poly (ADP-ribose) polymerase-1 (PARP-1). However, the underlying mechanisms and physiological significance of parthanatos are poorly understood. In this study, we investigated molecular mechanisms of parthanatos in human fibrosarcoma HT1080 cells using biochemical and cellular experiments, and found that parthanatos induced by the alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) is mediated by two alternative pathways that depend on pro-death Bcl-2 family proteins BAX/BAK or Bcl-2-interacting mediator of cell death (Bim). Moreover, we found that MNNG activates AMP-activated protein kinase (AMPK) through PARP-1-dependent ATP depletion, and then AMPK selectively downregulates MNNG-induced parthanatos mediated by Bim but not BAX/BAK. Under unstimulated conditions, expression levels of Bim were below the detection limit. Interestingly, MNNG strongly upregulated the protein expression levels of Bim, but only when the activation of AMPK was inhibited. These observations suggest that the AMPK signaling pathways activated by PARP-1-dependent ATP depletion limit parthanatos by blocking the Bim upregulation triggering Bim-mediated parthanatos. Thus, our results demonstrate a novel relationship between AMPK and parthanatos, which may provide insights into the physiological roles of parthanatos. Full article

Mitochondria play a central role in cellular bioenergetics. They contribute significantly to ATP production, which is essential for maintaining cells. They are also key mediators of various types of cell death, including apoptosis, necroptosis, and ferroptosis. Additionally, they are one of the main regulators of autophagy. This brief review focuses on BID, a molecule of the BCL-2 family that is often overlooked. The importance of the cardiolipin/caspase-8/BID-FL platform, which is located on the surface of the outer mitochondrial membrane and generates tBID, will be emphasized. tBID is responsible for BAX/BAK delocalization and oligomerization, as well as the transmission of death signals. New insights into the regulation of caspase-8 and BID have emerged, and this review will highlight their originality in the context of activation and function. The focus will be on results from biophysical studies of artificial membranes, such as lipid-supported monolayers and giant unilamellar vesicles containing cardiolipin. We will present the destabilization of mitochondrial bioenergetics caused by the insertion of tBID at the mitochondrial contact site, as well as the marginal but additive role of the MTCH2 protein, not forgetting the new players. Full article