Search Results (9,521)

Prostate cancer is one of the most common malignancies in men, and advanced or metastatic disease remains associated with substantial morbidity and mortality. Therapeutic progress in recent years has been driven by the introduction of targeted treatment strategies, notably poly (ADP-ribose) polymerase (PARP) inhibitors, prostate-specific membrane antigen (PSMA)–directed radioligand therapy (RLT), and androgen receptor pathway inhibitors (ARPIs). This review summarizes evidence from phase II and III clinical trials, meta-analyses, and real-world studies evaluating the efficacy, safety, and clinical integration of olaparib, lutetium (¹⁷⁷Lu) vipivotide tetraxetan, and abiraterone in advanced prostate cancer. Emphasis is placed on the practical clinical application of these agents, including patient selection, treatment sequencing, and combination strategies. PARP inhibition with olaparib has demonstrated clear benefits in metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) mutations, particularly BRCA1/2 alterations. PSMA-directed RLT offers a survival advantage in PSMA-positive mCRPC following AR pathway inhibition, with distinct toxicity considerations that influence patient selection. Abiraterone remains a cornerstone therapy across disease stages and plays an important role both as monotherapy and as a combination partner. Emerging data suggest a potential synergy between PARP inhibitors and AR-targeted agents, while also highlighting the limitations of biomarker-unselected approaches. We conclude that the optimal use of PARP inhibitors, PSMA-targeted RLT, and ARPIs requires a personalized strategy guided by molecular profiling, functional imaging, prior treatment exposure, and safety considerations. This clinically focused overview aims to support evidence-based decision-making in an increasingly complex treatment landscape. Full article

In today’s world, unhealthy living habits have contributed to the rise in metabolic disorders like hyperlipidemia. Recognized as a popular edible and medicinal mushroom in China and various eastern nations, Ganoderma lucidum is a promising high-value functional and medicinal food with multiple biological activities. Our earlier research has demonstrated that G. lucidum polysaccharides (GLP) showed distinct lipid-lowering abilities by enhancing the response to oxidative stress and inflammation, adjusting bile acid production and lipid regulation factors, and facilitating reverse cholesterol transport through Nrf2-Keap1, NF-κB, LXRα-ABCA1/ABCG1, CYP7A1-CYP27A1, and FXR-FGF15 pathways, hence we delved deeper into the effects of GLP on hyperlipidemia, focusing on its structural characterization, gut microbiota, and fecal metabolites. Our findings showed that GLP changed the composition and structure of gut microbiota, and 10 key biomarker strains screened by LEfSe analysis markedly increased the abundance of energy metabolism, and cell growth and death pathways which were found by PICRUSt2. In addition, GLP intervention significantly altered the fecal metabolites, which enriched in amino acid metabolism and lipid metabolism pathways. The results of structural characterization showed that GLP, with the molecular weight of 12.53 kDa, consisted of pyranose rings and was linked by α-type and β-type glycosidic bonds, and its overall morphology appeared as an irregular flaky structure with some flecks and holes in the surface. Collectively, our study highlighted that the protective effects of GLP were closely associated with the modification of gut microbiota and the regulation of metabolites profiles, thus ameliorating dyslipidemia. Full article

Background: Osteosarcoma (OSA) is the most common type of bone cancer in canines. Novel therapies are required to prevent the growth, survival, and metastatic progression of this cancer, to increase life expectancy of patients. Immunohistochemical (IHC) studies and RNA sequencing help us gain a deeper understanding into the molecular mechanisms of the disease. Methods: We previously compared canine OSA tissues with patient matched non-tumour tissues, revealing 442 overexpressed genes within the samples. The present research used IHC staining for four of these genes in OSA tissues: G protein-coupled receptor 64 (GPR64), TOX High Mobility Group Box Family Member 3 (TOX3), Matrix Metallopeptidase 12 (MMP-12), and Forkhead Box F1 (FOXF1). H-scoring was performed to quantitatively assess protein expression and qualitatively contextualise staining locations. Additional analyses addressed whether gender or anatomical location of lesions (axial or appendicular tumours) affected protein expression. cBioPortal was employed to analyse expression and genetic alterations in patients. Results: GPR64, TOX3, MMP-12, and FOXF1 showed high mRNA expression and genetic alterations in people with OSA. GPR64, TOX3, MMP-12, and FOXF1 were all expressed in canine OSA with novel findings regarding cellular expression. Additionally, differential sex expression was revealed for GPR64 and TOX3. Potential biomarkers or therapeutic targets were identified. Conclusions: These studies, and subsequent analysis, have provided insights into the molecular mechanisms associated with OSA progression and revealed potential biomarkers for diagnostic and prognostic purposes. A deeper understanding of genetic and protein interactions will support and progress novel pathways towards diagnostic, prognostic, and treatment interventions for OSA in both veterinary and human medicine. Full article

Methane (CH₄), a significant greenhouse gas, ranks second only to carbon dioxide in its contribution to global warming. The application of Chinese herbs as a strategy to mitigate CH₄ emissions in ruminants has shown promise. However, there is limited information regarding the efficacy of Chinese herb straw in reducing CH₄ emissions in ruminants. This research aimed to investigate the beneficial effects of varying levels of Astragalus straw supplementation on methane emissions and to elucidate the underlying molecular mechanisms. The study examined the effects of different supplementation levels (0%, 5%, 10%, 15%, 20%) on in vitro rumen fermentation, CH₄ emissions, and ruminal microbial community in Lanzhou fat-tailed sheep using an in vitro fermentation method. The findings indicated that IVDMD, gas production, and CH₄ production significantly decreased with increasing levels of Astragalus straw supplementation (p < 0.05). Simultaneously, the lowest levels of AA, AA/PA, and NH₃-N, along with the highest concentrations of PA, BA, and MCP, were observed in the 20% supplementation group after 48 h of fermentation. In addition, supplementation with Astragalus straw resulted in an increased abundance of Bacteroidota, Spirochaetota, and Actinobacteriota, while decreasing the abundance of Firmicutes, Fibrobacterota, and Verrucomicrobiota. At the genus level, there was an observed increase in the abundance of Prevotella and Streptococcus, accompanied by a decrease in Rikenellaceae_RC9_gut_group. In conclusion, the supplementation of Astragalus straw has the potential to reduce CH₄ production by altering ruminal fermentation patterns, fermentation parameters, and microbial dynamics. Full article

Background: Mechanical loading is a fundamental regulator of bone remodelling; however, the mechanotransduction mechanisms governing alveolar bone adaptation under tensile-dominant orthodontic loading remain insufficiently defined. In particular, the molecular pathways associated with tension-driven cortical modelling in the periodontal ligament (PDL)–bone complex have not been systematically interpreted in the context of advanced biomechanical simulations. Methods: A nonlinear finite element model of the alveolar bone–PDL–tooth complex was developed using patient-specific CBCT data. Three loading configurations were analysed: (i) conventional orthodontic loading, (ii) loading combined with corticotomy alone, and (iii) a translation-dominant configuration generated by the Bone Protection System (BPS). Pressure distribution, displacement vectors, and stress polarity within the PDL and cortical plate were quantified across different bone density conditions. The mechanical outputs were subsequently interpreted in relation to established mechanotransductive molecular pathways involved in osteogenesis and angiogenesis. Results: Conventional loading generated compression-dominant stress fields within the marginal PDL, frequently exceeding physiological thresholds and producing moment-driven root displacement. Corticotomy alone reduced local stiffness but did not substantially alter stress polarity. The BPS configuration redirected loads toward a tensile-favourable mechanical environment characterised by reduced peak compressive pressures and parallel (translation-dominant) displacement vectors. The predicted tensile stress distribution is compatible with activation profiles of key mechanosensitive pathways, including integrin–FAK signalling, Wnt/β-catenin–mediated osteogenic differentiation and HIF-1α/VEGF-driven angiogenic coupling, suggesting a microenvironment that may be more conducive to cortical apposition than to resorption. Conclusions: This study presents a computational–molecular framework linking finite element–derived tensile stress patterns with osteogenic and angiogenic signalling pathways relevant to alveolar bone remodelling. The findings suggestthat controlled redirection of orthodontic loading toward tensile domains may shift the mechanical environment of the PDL–bone complex toward conditions associated with osteogenic than resorptive responses providing a mechanistic basis for tension-induced cortical modelling. This mechanobiological paradigm advances the understanding of load-guided alveolar bone adaptation at both the tissue and molecular levels. Full article

Osteoporosis and chronic conditions such as type 2 diabetes mellitus, cardiovascular disease, heart failure, and chronic kidney disease share several common biological mechanisms, including chronic inflammation, oxidative stress, hormonal dysregulation, and metabolic alterations. In this context, multimorbidity presents an increasing clinical challenge, particularly in older populations, where osteoporosis remains frequently underdiagnosed and undertreated. This review aims to explore the complex interplay between skeletal fragility and cardiometabolic diseases, emphasizing the role of nutritional deficiencies (such as iron and vitamin C), shared molecular pathways (advanced glycation end-products, Renin–Angiotensin–Aldosterone System, RANK Ligand, RANK), and the systemic impact of chronic inflammation and tissue hypoperfusion. The review also addresses the effects of various drug classes—antidiabetics, antihypertensives, anticoagulants, and anti-osteoporotic agents—on bone metabolism and cardiovascular risk. Special focus is given to the implementation of integrated and personalized care models, particularly multidisciplinary team-based approaches, which have demonstrated significant reductions in mortality and refracture rates, despite their still limited adoption in clinical practice. In conclusion, this review highlights the shared mechanisms between osteoporosis and cardiometabolic conditions in the context of multimorbidity, underscoring persistent clinical challenges related to diagnosis, drug interactions, and care fragmentation that warrant further research into integrated care models. Full article

Background/Objectives: Cancer-associated fibroblasts (CAFs) are key stromal mediators of breast tumor progression and therapy resistance. Carvacrol, a dietary monoterpenic phenol, exhibits antiproliferative activity in cancer cells, but its effects on primary human breast CAFs remain unclear. This study aimed to determine whether carvacrol selectively induces mitochondria-related apoptotic signaling in breast CAFs while sparing normal fibroblasts (NFs). Methods: Primary fibroblast cultures were established from invasive ductal carcinoma tissues (CAFs, n = 9) and nonmalignant breast tissues (NFs, n = 5) and validated by α-SMA and FAP immunofluorescence. Cells were exposed to 400 μM carvacrol. Apoptosis was assessed by TUNEL assay and BAX/BCL-XL Western blotting. Changes in signaling pathways were evaluated by analyzing PPARα/NF-κB, sirtuin (SIRT1, SIRT3), autophagy-related markers (LAMP2A, p62), and matrix metalloproteinases (MMP-2, MMP-3). In silico molecular docking and 100-ns molecular dynamics simulations were performed to examine interactions between carvacrol and caspase-3 and caspase-9. Results: Carvacrol induced a pronounced, time-dependent apoptotic response in CAFs, with TUNEL-based viability declining to approximately 10% of control levels by 12 h and a marked increase in the BAX/BCL-XL ratio. In contrast, NFs exhibited minimal TUNEL positivity and no significant change in BAX/BCL-XL. In CAFs, but not NFs, carvacrol reduced PPARα expression and NF-κB nuclear localization, increased SIRT1 and SIRT3 levels, selectively suppressed MMP-3 while partially normalizing MMP-2, and altered autophagy-related markers (decreased LAMP2A and accumulation of p62), consistent with autophagic stress and possible impairment of autophagic flux. Computational analyses revealed stable carvacrol binding to caspase-3 and caspase-9 with modest stabilization of active-site loops, supporting caspase-dependent, mitochondria-related apoptosis. Conclusions: Carvacrol selectively targets breast cancer-associated fibroblasts by inducing mitochondria-related apoptotic signaling while largely sparing normal fibroblasts. This effect is accompanied by coordinated modulation of PPARα/NF-κB, sirtuin, autophagy, and MMP pathways. These findings support further evaluation of carvacrol as a microenvironment-directed adjunct in breast cancer therapy. Full article

Preeclampsia is a serious pregnancy disorder of unknown etiology. One of its cellular hallmarks is increased mitochondrial dysfunction in placental tissue. Further investigation into this aspect may help elucidate the molecular basis of preeclampsia. A total of 24 pregnant women who delivered by cesarean section participated in the study: n = 13 controls and n = 11 diagnosed with preeclampsia. Maternal blood samples were collected to assess the biochemical profile, and demographic and clinical data were recorded. Placental trophoblast samples were processed to isolate mitochondria and perform molecular biology assays. Women with preeclampsia exhibited the characteristic clinical features of the disease, along with biochemical alterations consistent with an inflammatory process. A significant decrease (73%) in mitochondrial DNA (mtDNA) copy number in trophoblastic tissue and a reduction in citrate synthase (CS) activity (−51%) in cytotrophoblast mitochondria-enriched fractions were observed in preeclampsia, indicating mitochondrial dysfunction accompanied by a loss of functional mitochondrial mass. In addition, we detected a marked decrease in MnSOD levels (−32%), together with an increase in the LC3II/LC3I ratio (47%) in cytotrophoblast mitochondria-enriched fractions, supporting the presence of mitochondrial alterations and suggesting the possible activation of mitophagy specifically in this cell type. Moreover, coenzyme Q₁₀ (CoQ₁₀) levels were elevated by 31% in trophoblastic villi. A pronounced 2.5-fold increase in CoQ₁₀ normalized to CS activity (CoQ₁₀/CS) was detected specifically in cytotrophoblasts from preeclamptic placentas. Importantly, we did not observe these alterations in the syncytiotrophoblast. In conclusion, preeclampsia is associated with mitochondrial dysfunction and increased CoQ₁₀ levels normalized to CS activity, specifically in cytotrophoblast mitochondria, with findings being consistent with a possible involvement of mitophagy in this cell type. These findings suggest that cytotrophoblast mitochondrial metabolism may be more affected in preeclampsia compared with syncytiotrophoblasts, and that CoQ₁₀ accumulation together with the possible activation of mitophagy may represent cellular defense mechanisms. Due to the limitations of the study, it should be considered exploratory and hypothesis-generating, and its results should be regarded as preliminary. Full article

Cervical cancer remains a major global public health concern, with persistent infection by high-risk human papillomavirus (hrHPV) types recognized as the primary etiological factor. This review explores the multifactorial nature of the disease, focusing on the complex interplay between host genetic susceptibility and epigenetic alterations that drive cervical carcinogenesis. Evidence from genome-wide association studies (GWAS) is discussed, highlighting the contribution of specific genetic loci, predominantly within the HLA region, to susceptibility to HPV infection and disease progression. In parallel, the review examines the molecular mechanisms by which the viral oncoproteins E6 and E7 promote genetic instability and epigenetic reprogramming, including histone modifications and dysregulation of non-coding RNAs. Particular emphasis is placed on DNA methylation, affecting both the viral genome and host genes such as FAM19A4, CADM1, PAX1, and MAL, as a promising biomarker for triage and detection of high-grade intraepithelial lesions (CIN2+). Finally, the review evaluates currently available methylation-based assays and self-sampling devices, highlighting their potential to enhance diagnostic accuracy and increase participation in cervical cancer screening programs. Full article

Background: The apicomplexan parasite Toxoplasma gondii causes serious diseases in animals and humans. The in vitro efficacy of the antimicrobial peptide mixture tyrothricin, composed of tyrocidines and gramicidins, against T. gondii tachyzoites was investigated. Methods: Effects against T. gondii were determined by monitoring inhibition of tachyzoite proliferation and electron microscopy, host cell and splenocyte toxicity was measured by Alamar blue assay, and early embryo toxicity was assessed using zebrafish embryos. Differential affinity chromatography coupled to mass spectrometry and proteomics (DAC-MS-proteomics) was employed to identify potential molecular targets in T. gondii cell-free extracts. Results: Tyrothricin inhibited T. gondii proliferation at IC₅₀s < 100 nM, with tyrocidine A being the active and gramicidin A the inactive component. Tyrothricin also impaired fibroblast, T cell and zebrafish embryo viability at 1 µM. Electron microscopy carried out after 6 h of treatment revealed cytoplasmic vacuolization and structural alterations in the parasite mitochondrion, but these changes appeared only transiently, and tachyzoites recovered after 96 h. Tyrothricin also induced a reduction in the mitochondrial membrane potential. DAC-MS-proteomics identified 521 proteins binding only to tyrocidine A. No specific binding to gramicidin A was noted, and four proteins were common to both peptides. Among the proteins binding specifically to tyrocidine A were several SRS surface antigens and secretory proteins, mitochondrial inner and outer membrane proteins associated with the electron transfer chain and porin, and several calcium-binding proteins putatively involved in signaling. Discussion: These results suggest that tyrocidine A potentially affected multiple pathways important for parasite survival and development. Full article

The zoonotic potential of bat coronaviruses, especially HKU5, is a significant issue because of their capacity to utilize human angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry. This study offers structural insights into the binding kinetics of HKU5 (Bat Merbecovirus HKU5) receptor-binding domain (RBD) spike protein with human ACE2 through a multiscale computational method. This study employed structural modeling, 300-nanosecond (ns) molecular dynamics (MD) simulations, alanine-scanning mutagenesis, and computational peptide design to investigate ACE2 recognition by the HKU5 RBD and its interactions with peptides. The root mean square deviation (RMSD) investigation of HKU5–ACE2 complexes indicated that HKU5 exhibited greater flexibility than SARS-CoV-2, with RMSD values reaching a maximum of 1.2 nm. Free energy analysis, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA), indicated a more robust binding affinity of HKU5 to ACE2 (ΔG_Total = −21.61 kcal/mol) in contrast to SARS-CoV-2 (ΔG_Total = −5.82 kcal/mol), implying that HKU5 binding with ACE2 had higher efficiency. Additionally, a peptide was designed from the ACE2 interface, resulting in the development of 380 single-site mutants by mutational alterations. The four most promising mutant peptides were selected for 300-nanosecond (ns) MD simulations, subsequently undergoing quantum chemical calculations (DFT) to evaluate their electronic characteristics. MM/GBSA of −37.83 kcal/mol indicated that mutant-1 exhibits the most favorable binding with HKU5, hence potentially inhibiting ACE2 interaction. Mutant-1 formed hydrogen bonds involving Glu74, Ser202, Ser204, and Asn152 residues of HKU5. Finally, QM/MM calculations on the peptide–HKU5 complexes showed the most favorable ΔE_interaction of −170.47 (Hartree) for mutant-1 peptide. These findings offer a thorough comprehension of receptor-binding dynamics and are crucial for evaluating the zoonotic risk associated with HKU5-CoV and guiding the design of receptor-targeted antiviral treatments. Full article

Three common agricultural beneficial microbes, Trichoderma harzianum, Bacillus cereus, and Pseudomonas fluorescens, are widely used in the growth cycle of crops, and increase the yield of agricultural products through disease prevention and sterilization. As a biodegradable biological macromolecular material, polylactic acid (PLA) is also widely used in agricultural production as a biodegradable film. The addition of agricultural microbes will affect the degradation rate of polylactic acid and thus its agricultural use. Under specific conditions (Tri15), the degradation rate of PLA film exceeds 30%. Scanning electron microscopy (SEM) images show that the degradation of the PLA happened after 360 days of exposure to these three specific microbe environments, which makes the surface of PLA films crack. Gel permeation chromatography (GPC) analysis reveals that in the presence of these microbes, the molecular weight of PLA is reduced. The analysis of 16S rDNA sequences demonstrates that the introduction of these microbes alters the soil microbial community, resulting in an enhanced abundance of Betaproteomicrobes, promoting the degradation of PLA. These results indicate that the three microbes species significantly promote the degradation of PLA, and the effects of microbes vary for the different concentrations. This study establishes practical guidelines for the deployment of PLA in real-world farmland environments. Full article

Thyroid cancer (TC) incidence is rising, necessitating a refined understanding of its complex biology, particularly for advanced forms. This review synthesizes the state-of-the-art knowledge, guided by the WHO 5th Classification (2022), which incorporates molecular findings and introduces categories like Differentiated High-Grade Thyroid Carcinoma (DHGTC) to better stratify prognosis. The review summarizes the molecular changes in thyroid cancer (TC) by establishing a clear link between specific oncogenic alterations and the resulting tumor phenotype, prognosis, risk stratification and therapeutic vulnerabilities. The central importance of the review lies in its comprehensive integration of these molecular changes with the resulting immunological microenvironment and the rationale for novel, personalized therapies. Moreover, high-level genomic instability within aggressive thyroid malignancies promotes an immunosuppressive tumor microenvironment via the selection and recruitment of suppressive immune components, contributing to immune evasion and poor prognosis. This characteristic immunosuppression identifies the aggressive tumors as prime candidates for targeted immunotherapies. The review implicitly argues that understanding the molecular drivers of this immunosuppression is essential for designing effective clinical trials using these novel agents. Diagnostic advancements, including molecular testing for high-risk mutations (BRAF, TERT) and the integration of Artificial Intelligence (AI) for refined risk stratification, are enabling personalized treatment. The evolving molecular and clinical understanding allows for a paradigm shift toward individualized therapies that balance optimal disease control with minimizing morbidity, especially in the context of high-risk disease. Full article

This study presents a practical and tunable 3D printing-based approach for manufacturing oral controlled-release bilayer tablets by modulating drug release solely through layer ratio control within a single dosage form. Theophylline-loaded filaments were prepared via hot-melt extrusion (HME) using Kollicoat^® IR or hydroxypropyl cellulose as polymer matrices. The mechanical properties of the manufactured filaments were evaluated and compared with commercial filaments to confirm their suitability for fused deposition modeling (FDM) printing. Physicochemical characterization using scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy indicated partial crystallinity and molecular dispersion of the drug within the polymer matrices. Using a dual-nozzle FDM 3D printer, five bilayer tablets composed of two drug-loaded filaments at different layer ratios were successfully fabricated without altering formulation composition or processing conditions. Drug release studies revealed distinct dissolution behaviors that were strongly dependent on the bilayer composition. Overall, this study demonstrates that controlled drug release can be effectively achieved through geometric modulation of bilayer structures using a combined HME–FDM 3D printing approach, providing a practical platform for personalized oral drug delivery without increasing formulation complexity. Full article

Background: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon and aggressive tumor for which the most effective systemic therapy remains uncertain. In metastatic LCNEC, chemotherapy approaches typically alternate between small-cell lung cancer (SCLC)-like and non-small-cell lung cancer (NSCLC)-like regimens. Emerging data indicate that treatment selection may be optimized through molecular subtype classification. This study aimed to evaluate the outcomes of SCLC-like and NSCLC-like chemotherapy (CT) regimens in relation to LCNEC molecular subtypes. Methods: This retrospective analysis included all patients diagnosed with LCNEC at Gaziantep University between January 2010 and October 2024. Individuals with available tumor tissue and complete clinical data were enrolled. LCNEC cases were categorized as SCLC-subtype or NSCLC-subtype according to the presence of TP53 and RB1 alterations. Platinum combined with etoposide, irinotecan, or topotecan was defined as SCLC-like CT, whereas platinum with taxanes or gemcitabine was considered NSCLC-like CT. Survival outcomes of both treatment types were compared across molecular subgroups using the Kaplan–Meier method. Results: Sixty-one patients met the inclusion criteria. The median overall survival (mOS) was 11.0 months (95% CI: 6.3–15.7). No significant difference in mOS was observed between SCLC-like and NSCLC-like regimens in the total cohort. When stratified by molecular subtype, patients with the SCLC subtype who received SCLC-like CT showed a longer mOS compared to those treated with NSCLC-like CT (15 [9.9–20.1] vs. 6 [3.9–8.1] months, respectively; p = 0.47), although this difference did not reach statistical significance. Conclusions: These findings suggest that molecular subclassification may help inform the choice of optimal systemic therapy in patients with LCNEC. Full article