Search Results (726)

The targeting of cyclin dependent kinase 8 (CDK8) as a potential strategy for cancer treatment has been of interest since the identification of CDK8 as an oncogene product. In this report, we communicate the results of our continuing investigation into the effects of CDK8 inhibitor on triple-negative breast cancer cell line MDA-MB-468. Here, we demonstrate that inhibition of CDK8 decreases phosphorylation of CDK8 substrates E2 promoter binding factor 1 (E2F1) at serine 375 and signal transducer and activator of transcription 3 (STAT3) at serine 727 in these cells. Additionally, luciferase expression was increased in E2F1-responsive luciferase plasmid-transfected cells. Expression of E2F1 transcription target, the proapoptotic protein p73, was increased, and expression of antiapoptotic protein myeloid cell leukemia sequence 1 (Mcl-1) was decreased in CDK8 inhibitor-treated cells. We also demonstrate that knockdown of STAT3 or disruption of STAT3 function in MDA-MB-468 cells opposes the effects of CDK8 inhibition on Mcl-1. Together, these results suggest that CDK8 inhibitor treatment can modulate the expression of apoptosis-related proteins p73 and Mcl-1 and continues to highlight the potential cooperative effects of E2F1 and STAT3 in the activity of CDK8 inhibitor against MDA-MB-468 triple-negative breast cancer cells. Full article

Background: The optimal timing and staging of anterior cruciate ligament reconstruction (ACLR) in patients with concomitant medial collateral ligament (MCL) injury remain controversial. This study aimed to compare clinical outcomes between a one-stage ACLR group and a two-stage ACLR group in patients with combined ACL and MCL injuries in which the MCL was surgically managed. Methods: This retrospective study included 68 patients with combined ACL and grade III MCL injuries treated with ACLR and MCL surgery. Patients were divided into the one-stage ACLR group (n = 42) and the two-stage ACLR group (n = 26) according to the timing and staging of ACLR relative to MCL surgery. Clinical outcomes, including knee stability, patient-reported outcomes, and range of motion (ROM), were compared between groups. Results: After a minimum 2-year follow-up, both groups demonstrated significant improvements in clinical and stability outcomes, with enhanced anterior knee stability, improved patient-reported outcomes, and better objectively assessed knee function. No significant differences were found between groups in anterior, valgus (one-stage: 1.8 ± 1.1 mm, two-stage: 2.3 ± 1.3 mm; p = 0.160), or rotational stability. Likewise, there were no significant differences in mean flexion deficits (one-stage: 2.6 ± 4.1°, two-stage: 1.0 ± 2.0°; p = 0.137), mean extension deficits (one-stage: 1.5 ± 2.5°, two-stage: 1.3 ± 2.0°; p = 0.137), flexion deficits ≥10° (one-stage: 9.5% [4/42], two-stage: 0%; p = 0.290), extension deficits ≥ 5° (one-stage: 9.5% [4/42], two-stage: 3.8% [1/26]; p = 0.642), or additional procedures for postoperative stiffness (one-stage: 16.7% [7/42], two-stage: 11.5% [3/26]; p = 0.730). Patient-reported outcomes, including the Lysholm and IKDC subjective scores, were also comparable between groups. Conclusions: Both the one-stage ACLR group and the two-stage ACLR group for surgically managed combined ACL and MCL injuries yielded comparable clinical and stability outcomes, suggesting that one-stage ACLR can be performed without an apparent increase in the risk of postoperative stiffness or ROM limitations. However, given the limited sample size, these results should be interpreted cautiously because the study may have been insufficiently powered to detect small clinically meaningful differences. Full article

Background: The anterior cruciate ligament (ACL) and medial collateral ligament (MCL) display strikingly different healing behaviors, despite their similar structural roles within the knee. The epiligament (EL)—a vascular and cellular envelope surrounding each ligament—has emerged as a critical determinant of repair capacity. The aim of this study was to perform a region-specific, comparative analysis of EL molecular profiles in the ACL and MCL to elucidate the mechanisms underlying their contrasting reparative outcomes. Methods: Human ACL and MCL specimens were obtained from 12 fresh knee joints. Immunohistochemical labeling for CD34, α-smooth muscle actin (α-SMA), and vascular endothelial growth factor (VEGF) was performed across proximal, mid-substance, and distal EL regions. Quantitative image analysis using IHC Profiler for ImageJ generated semiquantitative (negative, low-positive, positive) distributions, and inter-ligament comparisons were quantified using t-tests (p  <  0.05). Results: Distinct, region-specific EL signatures were identified. The ACL EL exhibited strong proximal α-SMA expression (0% neg/66.8% low+/33.2%+) and notable distal CD34 positivity (0% neg/83.3% low+/16.7%+), while VEGF expression was confined to the mid-substance (≈55% low+/26%+). In contrast, the MCL EL was largely negative for CD34 and VEGF across all regions, showing a homogeneous but functionally oriented α-SMA profile: proximally negative, sparse mid positivity, and high distal low-positive staining (93.4% low+). Differences in proximal and distal CD34 and α-SMA expression between the ACL and MCL were highly significant (p  <  0.0001–0.001), confirming a mechanistic divergence in EL organization. Conclusions: The ACL EL is regionally heterogeneous, vascularly biased, and enriched in contractile α-SMA+ cells, suggesting localized but poorly coordinated reparative potential. In contrast, the MCL EL is structurally uniform, with distributed α-SMA activity supporting stable wound contraction and tissue continuity, despite limited angiogenic signaling. These findings indicate that the ACL’s failure to heal is not attributable to the absence of progenitor or angiogenic factors, but rather to its fragmented spatial organization and dominant contractile phenotype. Therapeutically, preserving and modulating the EL, particularly its CD34+ and α-SMA+ compartments, could be key to enhancing intrinsic ACL repair and improving outcomes in ligament reconstruction and regeneration. Full article

Background: Mock circulatory loops (MCLs) are benchtop experimental platforms that reproduce key features of the human cardiovascular system, providing a safe, controlled, and reproducible environment for haemodynamic investigation. This scoping review aims to systematically map the current landscape of MCLs used for aortic simulation and identify major areas of application. Methods: A systematic search of PubMed, Scopus, and Web of Science identified original studies employing MCLs for aortic simulation. Eligible studies were categorized into predefined themes: (I) (bio)mechanical aortic characterization, (II) hemodynamics, (III) device testing, (IV) diagnostics, and (V) training. Data on MCL configurations, aortic models, and study objectives were synthesized narratively. Results: Eighty-four studies met the inclusion criteria. Twenty-five investigated aortic biomechanics, 23 hemodynamics, 22 device or product testing, 13 validated diagnostic imaging techniques, and one training application. Models included porcine (n = 22), human cadaveric (n = 7), canine (n = 1), ovine (n = 1), bovine (n = 1), and 3D-printed or molded aortic phantoms (n = 55). MCLs were employed to study parameters such as aortic stiffness, flow dynamics, dissection propagation, endoleaks, imaging accuracy, and device performance. Conclusions: This review provides a comprehensive overview of MCL applications in aortic research. MCLs represent a versatile pre-clinical platform for studying aortic pathophysiology and testing endovascular therapies under controlled conditions. Standardized reporting frameworks are now required to improve reproducibility and accelerate translation to patient-specific planning. Full article

Background: Mantle Cell Lymphoma (MCL) is an aggressive malignancy with variable clinical behavior, largely reflecting the underlying molecular heterogeneity. The genomic landscape of MCL encompasses gene mutations with strong prognostic implications and secondary genetic events, which are also implicated in the pathogenesis and prognosis of the disease. Methods: We evaluated the diagnostic samples of 73 patients with relapsed/refractory MCL that were enrolled in the Fondazione Italiana Linfomi Mantle First-BIO study. All patients had available data for correlating CNVs with the presence of TP53 mutation. Time to first relapse or progression of disease (POD) was used as the primary outcome measure. Results: We identified CNVs associated with MCL, with Del 9p21.3 (CDKN2A) being the strongest predictor of shorter time to POD (p = 0.01), independently of TP53 mutation in multivariable analysis. Unsupervised clustering identified molecularly defined clusters that were associated with significantly different times to POD (p = 0.01). Pairwise log-rank tests confirmed TP53 mutated vs. wild-type (WT) as the strongest prognostic factor, with cluster assessment improving the prognostic predictivity among patients: clusters TP53-mut vs. TP53-WT, p = 0.001, HR = 3.92; and p = 0.014, HR = 2.23, respectively. In conclusion, CNV-based molecular clusters might represent a novel approach to identify patients at higher risk of treatment failure, further contributing to the prognostic predictivity of TP53 mutation. Full article

This study describes a series of water-soluble half-sandwich ruthenium(II), rhodium(III), and iridium(III) complexes with α-diimine ligands containing substituted aromatic groups. These ligands were derived from glyoxal and 2-aminophenol (a), 4-methyl-2-aminophenol (b), 4-aminophenol (c), phenyl hydrazine (d), and 1-aminonaphthalene (e). The ruthenium(II) (1b–1e), rhodium(III) (2a–2c, 2e), and iridium(III) complexes (3a–3e) were obtained by reacting the ligands (a–e) with the corresponding dimeric precursor [(η⁶-p-cym)RuCl₂]₂ (p-cym = p-cymene) or [(η⁵-Cp*)MCl₂]₂ (Cp* = pentamethylcyclopentadienyl, M = Rh, Ir) in air and under nonanhydro conditions. The air-stable and water-soluble ruthenium(II), rhodium(III), and iridium(III) complexes were characterized via nuclear magnetic resonance spectroscopy and electrospray ionization–mass spectrometry. The structures of complexes [(η⁶-p-cym)Ru(d)Cl]Cl, 1d; [(η⁵-Cp*)Ir(a)Cl]Cl, 3a; and [(η⁵-Cp*)Ir(c)Cl]Cl, 3c were determined via single-crystal X-ray diffraction. Additionally, the complexes exhibited catalytic activity as precatalysts in formic acid decomposition. Complex [(η⁵-Cp*)Ir(d)Cl]Cl, 3d achieved turnover number (TON) and turnover frequency (TOF) values of up to 2150 and 3861 h⁻¹, respectively, at short reaction times. In the hydrogenation of carbon dioxide, [(η⁶-p-cym)Ru(e)Cl]Cl, 1e attained TON and TOF values of up to 1385 and 69.25 h⁻¹, respectively. Full article

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) whose clinical course is largely shaped by molecular and biological features. Among the most impactful prognostic markers, TP53 mutations have emerged as critical determinants of treatment resistance since their first identification in MCL in 1996. Regardless of the detection method, TP53 mutations have been consistently associated with primary refractoriness to chemoimmunotherapy and significantly reduced overall survival. In this perspective, we explored recent advances in applying integrated-omics approaches to assess TP53 status. Despite its prognostic value, routine testing for TP53 at diagnosis remains uncommon, hindered by the lack of standardized protocols and costs for Next-Generation Sequencing (NGS), and the suboptimal reliability of immunohistochemistry (IHC) as a surrogate. This gap between research evidence and clinical practice represents a critical barrier to risk-adapted therapy. The broad implementation of standardized and accessible genomic techniques is essential to identify patients who deserve a personalized therapeutic approach. Several clinical trials have recently explored alternative chemo-free or targeted regimens specifically tailored to TP53-mutated patients (i.e., NCT03824483, NCT03567876), with promising results. This risk-adapted approach reflects a paradigm shift in MCL management, emphasizing the need for early molecular risk assessment to guide treatment decisions. In this scenario, TP53 mutations are no longer supporting actors, but a game-changer for the prognosis and treatment of patients with MCL. Full article

Despite advances with novel targeted agents (e.g., BCL-2 or IDH inhibitors) combined with chemotherapy for acute myeloid leukemia (AML), drug resistance persists. We investigated whether blocking Na⁺/H⁺ exchanger 1 (NHE1) could enhance AML cell sensitivity to the BCL-2 inhibitor venetoclax and sought to determine the molecular mechanisms. Our results demonstrated that co-treatment with venetoclax and the NHE1 inhibitor 5-(N,N-hexamethylene) amiloride (HMA) synergistically induced apoptosis in both venetoclax-sensitive and -resistant leukemic cell lines. Specifically, the combination significantly increased apoptosis in venetoclax-resistant THP-1 cells to 72.28% (17.79% with 100 nM venetoclax and 10.15% with 10 μM HMA alone; p < 0.001). Conversely, another venetoclax-resistant line, U-937, showed no significant apoptotic response to the combination. In THP-1 cells, this synergy was mediated via a caspase-dependent programmed cell death pathway, evidenced by an increased BAX/BCL-2 ratio, mitochondrial cytochrome c release, and subsequent caspase-9 and caspase-3 activation. Furthermore, co-treatment downregulated the anti-apoptotic protein MCL-1 and reduced PI3K and Akt phosphorylation, suggesting that inhibition of these survival pathways also contributed to the synergistic effect. Inhibition of NHE1 may substantially enhance venetoclax sensitivity in certain AML models, particularly in venetoclax-resistant THP-1 cells but not in U-937, highlighting biological diversity and the probable involvement of alternative survival pathways. Full article

Cyclic nitramine explosives such as octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), and 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) are xenobiotics that are utilized in a variety of propellants and traditional weapons. The primary source of water contamination is the industrial use of these hazardous substances in propellants and wastewater generated from munitions production facilities. These chemicals have a negative impact on human health and ecosystems. It is necessary to remove these toxic compounds from the environment safely because their production and usage have seriously contaminated soil and groundwater. Although there are no widely adopted WHO or US federal Maximum Contaminant Levels (MCLs) for military explosives, the health advisory limits for RDX in drinking water are 2 µg/L, and for HMX are 400 µg/L. Numerous traditional treatment approaches that incorporate physical, biological, and chemical processes have been used to decontaminate explosive wastewater. However, contaminants are not completely mineralized by these methods. Complete reduction of these chemicals can be accomplished by combining suitable methods. For the remediation of explosive effluent, integrated treatment systems that combine the effectiveness of biological and physical-chemical methods have shown promising results. This review discusses the toxicity and some physical–chemical–biological and combined treatment processes of wastewater polluted by these explosive contaminants. Full article

Passion fruit (Passiflora edulis f. flavicarpa), commonly known as yellow passion fruit, is widely grown across tropical and subtropical regions worldwide, with Brazil as one of the top producers. Mexico also produces a significant amount of this variety, mainly for juices, jams, or flavoring in desserts. Since this fruit is highly perishable with a short shelf life, it needs to be consumed or used quickly. Although different preservation methods have been suggested, no structural analyses of the peel have been performed to improve these processes. This study aimed to analyze the structural and chemical properties of the peel’s cuticular matrix to better understand water loss. CPMAS ¹³C NMR analysis revealed a matrix containing polysaccharides, a small amount of aliphatics, and a notable group of aromatic signals that may indicate lignin presence. This was supported by alkaline hydrolysis, which achieved only 30% hydrolysis. Soluble compounds identified included hexoses, palmitic acid, stearic acid, and derivatives of ferulic and caffeic acids, the latter being parts of lignin monomers. MCL and SEM analyses showed features similar to cutans, including pores along the structures. The BET surface area measurement indicated that the insoluble cuticular material (ICM) has a significant specific surface area. The lignin in the yellow passion fruit peel gives the shell toughness, which, along with its pores, may contribute to dehydration and a short shelf life. Full article

Marine-derived secondary metabolites have emerged as a rich potential source of anticancer agents, with marinopyrroles and pyrrolomycins representing structurally distinct halogenated pyrroles of interest. Initially characterized for their potent antibacterial properties, these compounds were later shown to exert cytotoxic activity across diverse hematologic and solid malignancies, frequently correlating with Mcl-1 dependence. Marinopyrrole A, a marine-derived natural product, exemplified this potential by inducing proteasomal degradation of Mcl-1, thereby sensitizing resistant cancer cells to Bcl-2 inhibitors and TRAIL-based therapies. In parallel, pyrrolomycins, particularly pyrrolomycin C and members of the F-series, demonstrated potent activity with submicromolar IC₅₀ concentrations across multiple cancer cell lines, and also perturbed cytoskeletal and membrane integrity. Together, these halogenated pyrroles illustrate multifaceted cancer cell cytotoxicity profiles but face translational barriers, including mechanistic ambiguity, poor solubility, and off-target toxicities. To address these limitations, extensive medicinal chemistry efforts have yielded synthetic derivatives with improved potency, selectivity, and drug-like properties, with notable examples such as MP1 and KS18 showing enhanced efficacy in MYC-driven neuroblastoma, medulloblastoma, and drug-resistant multiple myeloma. Full article

This study aimed to minimize the amount of gelator used in oleogel preparation and enhance the valorization of rubber seeds. Cellulose extracted from rubber seed shells was modified via high-pressure microfluidization (HPM), which significantly enhanced its specific surface area from 0.92 m²/g (CL) to 6.47 m²/g (MCL), along with markedly improved water-holding capacity (WHC increased from 4.92 to 29.37 g/g) and swelling capacity (SC increased from 0.65 to 3.38 mL/g). The modified cellulose (MCL) served as the gelator, while rubber seed oil bodies (OBs), isolated through sucrose-assisted extraction, functioned as the oil phase. A series of OB emulsions containing 0% to 0.75% MCL were prepared and subsequently converted into oleogels by freeze-drying and shearing. Oleogels containing ≥0.45% MCL exhibited excellent oil binding capacity (OBC > 98.6%) and strong gel strength (storage modulus G′ > 10⁵ Pa). Texture profile analysis further confirmed significant improvements in the textural properties of the oleogels with increasing MCL content. These findings demonstrate that MCL, combined with rubber seed OBs, enables the development of high-performance oleogels with minimal gelator requirements. This approach not only reduces gelator usage but also provides a novel strategy for the upcycling of rubber seed shells, offering valuable insights for the design of nutrient-rich functional oleogels. Full article

The BCL2 family of proteins plays a pivotal role in regulating apoptosis and cellular homeostasis, making them critical therapeutic targets in cancer and other diseases characterized by pathological cell survival. BH3 mimetics, small molecules that selectively inhibit anti-apoptotic BCL2 family members, have achieved significant clinical success, particularly in hematologic malignancies. However, several challenges remain, including resistance mechanisms, toxicity (such as MCL1 inhibitor-associated cardiotoxicity), and the intricate balance between apoptotic and non-apoptotic functions. This review provides a comprehensive overview of BCL2 family biology, the development and clinical application and outcomes of BH3 mimetics, and the emerging resistance mechanism known as double-bolt locking. We also examine strategies to overcome resistance, including combination therapies and immunomodulatory approaches. Beyond oncology, we highlight the expanding therapeutic potential of BH3 mimetics in autoimmune, fibrotic, and infectious diseases, as well as regenerative and anti-aging medicine. Finally, we discuss predictive biomarkers and tissue-specific responses that inform precision therapy. Together, these insights underscore the promise of BH3 mimetics and the need for continued multidisciplinary research to optimize their clinical impact. Full article

The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function (“OXPHOS-high” cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, suggestive of increased mitochondrial fusion. A genome-wide CRISPR editing screen in doxorubicin-persistent OXPHOS-high TNBC cells revealed the BCL-XL gene as the top survival dependency in these quiescent tumor cells, but not in their untreated proliferating counterparts. Quiescent OXPHOS-high TNBC cells were highly sensitive to BCL-XL inhibitors, but not to inhibitors of BCL2 and MCL1. Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis-targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy. Full article

Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and a poor prognosis. Natural phytochemicals from Dendrobium species, particularly bibenzyl derivatives, possess diverse pharmacological activities, yet their potential against GBM remains largely unexplored. Here, we investigated the anticancer activity of 4,5,4′-trihydroxy-3,3′-dimethoxybibenzyl (TDB), a potent antioxidant bibenzyl derivative isolated from Dendrobium pachyglossum. In U87MG cells, TDB reduced viability in a dose- and time-dependent manner, suppressed clonogenic growth, induced apoptosis via Bax upregulation and Bcl-xL/Mcl-1 downregulation, and inhibited both mTORC1 and mTORC2 signaling. TDB also impaired cell migration and downregulated epithelial–mesenchymal transition (EMT)-associated proteins. Notably, TDB enhanced the cytotoxicity of temozolomide (TMZ), the current standard of care for GBM. These TMZ-sensitizing properties were further confirmed in patient-derived xenograft (PDX) Jx22 cells. To assess its potential for central nervous system delivery, blood–brain barrier (BBB) permeability was predicted using four independent in silico platforms—ADMETlab 3.0, LogBB_Pred, LightBBB, and BBB Predictor (Tree2C)—all of which consistently classified TDB as BBB-permeable. This predicted CNS accessibility, together with its potent anticancer profile, underscores TDB’s translational promise. Collectively, our findings identify TDB as a plant-derived antioxidant with multifaceted anti-GBM activity and favorable BBB penetration potential, warranting further in vivo validation and preclinical development as a novel therapeutic candidate for GBM. Full article