Search Results (1,966)

Dorsomorphin, a pyrazolo[1,5-a]pyrimidine derivative, inhibits the bone morphogenetic protein (BMP) pathway by targeting the type I BMP receptors active in receptor-like kinases. However, the investigation of its—and its derivatives’—antiproliferative activity towards endothelial and cancer cell lines still requires reinforcement with additional studies. In the presented work, several dorsomorphin derivatives have been efficiently synthesized, based on a previously reported synthetic protocol with minor modifications. The endeavor was reinforced by a molecular docking study on the interactions of the designed derivatives with various protein targets, while the inhibitory effects of the synthesized novel molecules on the proliferation of murine leukemia cells (L1210), human T-lymphocyte cells (CEM), human cervix carcinoma cells (HeLa), and endothelial cells (human dermal microvascular, HMEC-1, and bovine aortic endothelial cells, BAECs) were investigated. Among the compounds tested, diphenol 22, emerged as the most promising bioactive lead since it demonstrated half-maximal inhibitory concentration (IC₅₀) values below 9 μM in all tested lines except HeLa cells. In the same context, the carbamate derivative 6 was determined as a potent inhibitor of endothelial cell proliferation in BAECs at a low micromolar range. In conclusion, the presented work not only reveals promising antiproliferative dorsomorphin derivatives but also sets the basis for further exploitation of dorsomorphin’s bioactive portfolio, based on bioactivity results and molecular modeling calculations. Full article

Extracellular vesicle (EV)-based therapies have emerged as promising, cell-free approaches for dental tissue regeneration. This narrative review integrates mechanistic insights, therapeutic efficacy data, and safety and delivery considerations from in vitro and in vivo studies to elucidate the molecular mechanisms by which EVs, particularly those from dental pulp stem cells (DPSCs) and mesenchymal stem cells (MSCs), drive regenerative processes via key signalling axes (PI3K/Akt, MAPK, BMP/Smad, and Hedgehog). Preclinical studies demonstrate that unmodified and engineered EVs enhance odontogenic differentiation, angiogenesis, bone repair, and immunomodulation in models of pulp regeneration, alveolar bone defects, osteonecrosis, and periodontitis. Isolation and purification methodologies were also evaluated, comparing ultracentrifugation, size-exclusion chromatography, and density-cushion approaches, and discussing how protocol variations affect EV purity, dosing metrics, and functional reproducibility. Early-phase clinical evaluations report only low-grade transient adverse events, underscoring a generally favourable safety profile. Despite these encouraging results, significant challenges remain: heterogeneity in EV cargo composition, lack of standardised potency assays, and incomplete long-term safety data. The review highlights the urgent need for rigorous, harmonised regulatory frameworks and robust quality control measures to ensure that EV-based modalities can be translated into safe, effective, and reproducible therapies in regenerative dentistry. Full article

Women of reproductive age, especially those with polycystic ovarian syndrome (PCOS), often use glucagon-like peptide-1 receptor agonists (GLP-1RAs) to improve their metabolic functions. A growing body of evidence suggests that GLP-1R signaling may directly affect ovarian physiology, influencing granulosa cell proliferation, survival pathways, and steroidogenic production, in addition to its systemic metabolic effects. Nonetheless, there is a limited comprehension of the molecular mechanisms that regulate these activities and their correlation with menstrual function, reproductive potential, and assisted reproduction. This comprehensive review focuses on ovarian biology, granulosa cell signaling networks, steroidogenesis, and translational fertility outcomes, integrating clinical, in vivo, and in vitro information to elucidate the effects of GLP-1 receptor agonists on reproductive health. We conducted a thorough search of PubMed, Scopus, and Web of Science for randomized trials, prospective studies, animal models, and cellular experiments evaluating the effects of GLP-1RA on reproductive or ovarian outcomes, in accordance with PRISMA criteria. The retrieved data included metabolic changes, androgen levels, monthly regularity, ovarian structure, granulosa cell growth and death, FOXO1 signaling, FSH-cAMP-BMP pathway activity, and fertility or IVF results. Clinical trials shown that GLP-1 receptor agonists improve menstrual regularity, decrease body weight and central adiposity, increase sex hormone-binding globulin levels, and lower free testosterone in overweight and obese women with PCOS. Liraglutide, when combined with metformin, significantly improved IVF pregnancy rates, whereas exenatide increased natural conception rates. Mechanistic studies demonstrate that GLP-1R activation affects FOXO1 phosphorylation, hence promoting granulosa cell proliferation and anti-apoptotic processes. Incretin signaling altered steroidogenesis by reducing the levels of StAR, P450scc, and 3β-HSD, so inhibiting FSH-induced progesterone synthesis, while simultaneously enhancing BMP-Smad signaling. Animal studies demonstrated both beneficial (enhanced follicular growth, anti-apoptotic effects) and detrimental results (oxidative stress, granulosa cell death, uterine inflammation), indicating a context- and dose-dependent response. GLP-1 receptor agonists influence female reproductive biology by altering overall physiological processes and specifically impacting the ovaries via FOXO1 regulation, steroidogenic enzyme expression, and BMP-mediated FSH signaling. Preliminary clinical data indicate improved reproductive function in PCOS, as seen by increased pregnancy rates in both natural and IVF cycles; nevertheless, animal studies reveal a potential risk of ovarian and endometrial damage. These results highlight the need for controlled human research to clarify reproductive safety, molecular pathways, and optimum therapy timing, particularly in non-PCOS patients and IVF settings. Full article

Background/Objectives: Autologous dentin matrix (ADM) has been suggested as a biologically plausible biomaterial for alveolar bone regeneration after tooth extraction. However, clinical evidence regarding its biological activity and early healing outcomes is limited. This exploratory, randomized controlled pilot study aimed to descriptively assess early alveolar healing patterns and bone morphogenetic protein 4 (BMP4) expression following tooth extraction using ADM compared with other grafting approaches. Methods: Patients requiring tooth extraction were allocated to one of four groups: ADM, xenograft, ADM combined with platelet-rich fibrin, and a graft-free control group. Histological and immunohistochemical analyses were performed four months after extraction to descriptively assess cellular features of healing and BMP4 expression. The trial was registered at the Brazilian Registry of Clinical Trials (ReBEC; RBR-24mdgrf) and conducted under prior ethics committee approval. Results: BMP4 expression was detected in 67.9% of the analyzed histological fields, predominantly localized in osteocytic, osteoblastic, and medullary areas. Although descriptive differences in BMP4-positive fields were observed among the groups, no statistically significant differences were identified between the groups. Histological evaluation revealed an active cellular environment across all treatment modalities, consistent with early post-extraction healing. No adverse events related to surgical procedures or grafting materials were reported during the study period. Conclusions: Within the limitations of this pilot randomized clinical trial, ADM exhibited consistent biological behavior during early post-extraction alveolar healing. The observed BMP4 expression likely reflects a general physiological healing response rather than a material-specific effect. This finding supports the biological plausibility of dentin-derived grafts as osteoconductive biomaterials. These findings are hypothesis-generating, and larger, adequately powered randomized clinical trials with standardized molecular and histological assessments are required to determine their clinical relevance. Full article

Obesity has reached epidemic proportions, driven by energy imbalance and limited capacity for adaptive thermogenesis. Brown (BAT) and beige adipose tissues dissipate energy through non-shivering thermogenesis (NST), primarily via uncoupling protein-1 (UCP1), making them attractive targets for increasing energy expenditure (EE). The canonical β-adrenergic pathway robustly activates NST in rodents through β3 adrenoceptors; however, translational success in humans has been limited by low β3 expression, off-target cardiovascular effects, and the emerging dominance of β2-mediated signaling in human BAT. Consequently, attention has shifted to non-adrenergic and UCP1-independent mechanisms that offer greater tissue distribution and improved safety profiles. This review examines a broad spectrum of alternative receptors and pathways—including GPRs, TRP channels, TGR5, GLP-1R, thyroid hormone receptors, estrogen receptors, growth hormone, BMPs, sirtuins, PPARs, and interleukin signaling—as well as futile substrate cycles (Ca²⁺, creatine, and glycerol-3-phosphate) that sustain thermogenesis in beige adipocytes and skeletal muscle. Pharmacological agents (natural compounds, peptides, and small molecules) and non-pharmacological interventions (cold exposure, exercise, diet, and time shift) targeting these pathways are critically evaluated. We highlight the translational gaps between rodent and human studies, the promise of multimodal therapies combining low-dose adrenergic agents with non-adrenergic activators, and emerging strategies such as sarco/endoplasmic reticulum calcium ATPase protein (SERCA) modulators and tissue-specific delivery. Ultimately, integrating adrenergic and non-adrenergic approaches holds the greatest potential for safe, effective, and sustainable obesity management. Full article

Cervical cancer remains a significant global health burden, with chemoradioresistance representing a major obstacle to successful treatment. To elucidate the mechanisms underlying this resistance, we established a unique pair of isogenic primary cervical cancer cell lines, AdMer35 and AdMer43, obtained from a patient with squamous cell carcinoma of the cervix before and after radiation therapy. The aim of our study was to characterize the transcriptomic and cellular heterogeneity of these cells. We conducted an in-depth comparative analysis using single-cell RNA sequencing. Analysis of this paired, patient-derived isogenic model suggests that chemoradioresistance can arise through coordinated multilevel cellular adaptations. Resistant AdMer43 cells demonstrated transcriptional reprogramming, with the upregulation of embryonic stemness factors (HOX, POU5F1, SOX2), a shift in extracellular matrix from fibrillar to non-fibrillar collagens, and activation of inflammatory pathways. We identified and characterized critical cell-state dynamics: resistant cells exhibited a remodeled ecosystem with a metabolically reprogrammed senescent-like cell population showing an enhanced pro-tumorigenic communication via EREG, SEMA3C, BMP, and WNT pathways. Furthermore, we identified a progenitor-like cell population with a minimal CNV burden, potentially serving as a reservoir for tumor persistence. These findings offer novel insights for developing targeted strategies to eliminate resistant cell pools and improve cervical cancer outcomes. Full article

Calcific aortic valve stenosis (CAVS) is a progressive cardiovascular disease associated with oxidative stress-driven osteogenic differentiation of valvular interstitial cells (VICs), yet no pharmacological therapy can prevent its progression. γ-oryzanol (γ-ORZ), a rice bran-derived phytosteryl ferulate, exhibits potent antioxidative and anti-inflammatory activities that may counteract valvular calcification. Here, we show that γ-ORZ markedly attenuates PCM-induced intracellular ROS elevation, osteogenic differentiation, and calcium phosphate deposition in porcine VICs (pVICs). In addition, RT-qPCR and Western blot analyses revealed significant downregulation of calcification markers (RUNX2, OPN, BMP2), along with suppressed SMAD1/5/9 transcription and phosphorylation, decreased p38/ERK MAPK activation, and reduced ALP activity. Collectively, these findings indicate that γ-ORZ mitigates oxidative stress-mediated valvular calcification by inhibiting both canonical and non-canonical BMP2-SMAD/MAPK signaling, suggesting its potential as a medicinal candidate for early intervention in CAVS. Full article

Tuna-processing facilities produce substantial amounts of concentrated organic residues and sludges containing high levels of proteins, lipids, and nitrogen, which are not easily handled by conventional waste treatment methods. In this work, the anaerobic digestion (AD) performance of tuna-processing by-products (TPB1–2) and associated wastewater sludges (TWS1–3) was investigated using a combination of biochemical methane potential (BMP) tests, theoretical methane yield calculations based on the Buswell–Boyle equation, semi-continuous mono-digestion experiments, and 16S rRNA gene-based microbial analyses. Among the evaluated materials, TWS2 produced the highest methane yield (554.6 N mL CH₄/g VS) and, when its annual production volume was taken into account, showed the greatest estimated energy recovery (approximately 1.88 × 10⁶ kWh per year). By contrast, TWS3 exhibited the lowest methane yield (239.8 N mL CH₄/g VS), which was attributed to the presence of lignocellulosic sawdust and its limited biodegradability. TWS1 showed a moderate level of performance, with an estimated biodegradability of 62.3%, which may have been influenced by the addition of ferric salts and polymeric coagulants during sludge conditioning. In the semi-continuous digestion experiments, reactors that were initiated under relatively high total ammonia nitrogen (TAN) concentrations achieved stable operation within a shorter period, with the acclimation phase reduced by approximately one hydraulic retention time. These trends were supported by the microbial community data, where an increase in Bacillota-associated families, such as Tissierellaceae and Streptococcaceae, was detected along with a clear shift in dominant methanogens from Methanothrix to the more ammonia-tolerant Methanosarcina. Taken together, it is suggested that, when ammonia levels are appropriately managed, mono-digestion of tuna-processing sludges can be operated at a moderate organic loading rate. The process stabilization and energy recovery in nitrogen-rich industrial wastes are closely linked to gradual microbial adaptation rather than immediate improvements in methane yield. Full article

The complexity of cell fate decisions that underpin early eye development can be effectively modelled by leveraging the unique properties of human induced pluripotent stem cells (hiPSCs). In this study, we have utilised transcriptomic data generated from hiPSCs as they begin to self-organise and differentiate into two-dimensional eye-like organoids in vitro, and employ advanced single-cell analytical tools to dissect the cellular communication networks that direct this dynamic process. We have identified key signalling mediators and transcriptional effectors that guide the transition from pluripotency through to ocular differentiation, and our analyses reveal the conservation of developmentally defined signalling pathways. Members of the Activin, FGF, BMP, WNT, and retinoic acid families of ligands and receptors displayed communication probabilities consistent with their ocular-specific developmental roles in vivo, and this was accompanied by conserved tissue-specific activity of transcriptional regulators. These findings not only highlight the utility of hiPSCs for studying the cellular interactions and molecular pathways that drive early developmental decisions, but also advance our understanding of eye development in an accessible stem cell-based system. Full article

The Yucatán Black Hairless Pig (YBHP) is an indigenous Mexican breed shaped by tropical environments and traditional management systems. This study aimed to characterize its runs of homozygosity (ROH) and compare its ROH patterns with those of indigenous and commercial pig breeds worldwide using the GGP Porcine 50K SNP array. After applying standard quality-control filters, ROH were identified, classified by length, and evaluated for shared homozygous regions across populations. The YBHP showed intermediate levels of genomic homozygosity (FROH = 0.09), with most ROH segments falling within the 5–20 Mb range. Comparative analyses indicated that the YBHP shared a higher number of ROH segments with indigenous populations than with cosmopolitan breeds. Gene annotation within ROH regions revealed SNPs located in genes previously reported in indigenous populations, including FGF5, BMP2K, PAQR3, RASGEF1B and ANTXR2, which participate in developmental and regulatory biological pathways. Overall, these results provide a detailed description of ROH distribution in the YBHP and offer complementary information to previous studies on its genetic characterization, supporting future conservation and management strategies. Full article

Testosterone (T) produced by Leydig cells (LCs) is essential for male reproduction; yet, the regulatory mechanisms underlying steroidogenesis remain incompletely understood. Here, we investigated the role of cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) in Leydig cell development and steroidogenesis, based on its identification by immunoprecipitation-mass spectrometry (IP-MS) as a protein associated with steroidogenesis and cholesterol metabolism in mouse testicular tissue. Using human samples, we found that CDK5RAP3 expression was significantly reduced in Leydig cells from patients with spermatogenic failure (T < 10.4 nmol/L). Notably, CDK5RAP3 expression increased during mouse postnatal Leydig cell maturation and regeneration in an ethane dimethanesulfonate (EDS)-induced rat model. Functional analyses in primary LCs and MLTC-1 cells showed that hCG stimulation triggered CDK5RAP3 nuclear translocation without altering its overall expression, while CDK5RAP3 knockdown markedly impaired hCG-induced testosterone production and reduced the expression of the steroidogenic regulator steroidogenic acute regulatory (STAR) protein, as well as key steroidgenic enzymes, including cytochrome P450 family 11 subfamily A member 1 (CYP11A1), 17a-hydroxylase (CYP17A1), and 3β-hydroxysteroid dehydrogenase (HSD3B). Conversely, CDK5RAP3 overexpression enhanced testosterone production in the absence of hCG. In vivo, AAV2/9-mediated CDK5RAP3 silencing in adult mouse testes resulted in a significant reduction in serum testosterone levels compared with controls (3.60 ± 0.38 ng/mL vs. 1.83 ± 0.37 ng/mL). Mechanistically, CDK5RAP3 interacted with SMAD4 and CEBPB, and BMP pathway inhibition by Noggin rescued the testosterone deficit caused by CDK5RAP3 loss. Together, these findings identify CDK5RAP3 as an essential regulator of Leydig cell steroidogenesis and provide insight into its potential relevance to male infertility associated with low testosterone. Full article

The global floriculture industry generates massive organic residues that pose environmental risks but offer untapped bioenergy potential. This review evaluates the feasibility of valorizing flower waste through anaerobic digestion (AD) by synthesizing experimental data on substrate characterization, pretreatment efficacy, and reactor performance. Results indicate that biochemical methane potentials (BMP) vary significantly, ranging from 89 to 412 mL_CH4·g⁻¹_VS, depending on plant species and tissue composition. Major bottlenecks include high lignocellulosic recalcitrance (lignin content up to 0.28 g·g⁻¹_TS) and the presence of inhibitory phenolic compounds. Analysis reveals that while alkaline pretreatments effectively disrupt lignocellulosic structures, co-digestion strategies are essential to mitigate inhibition and balance nutrient ratios. However, current research is predominantly limited to laboratory-scale batch assays, leaving a critical knowledge gap regarding long-term process stability and inhibition dynamics in continuous systems. To transform this laboratory concept into a scalable technology, future efforts must focus on pilot-scale continuous reactor trials, standardized testing protocols, and comprehensive techno-economic and life cycle assessments. Full article

This paper proposes an optimized digital predistortion (DPD) framework. Firstly, a peak-detection-based loop-delay estimation is developed by leveraging the unique peak distribution of Orthogonal Frequency Division Multiplexing (OFDM) signals. It reduces the required number of samples to as small as two without compromising estimation accuracy. Then, a Biased Memory Polynomial (BMP) model is proposed for power amplifier modeling. It addresses low-power inaccuracies caused by circuit imperfections (e.g., DC offsets) by adding a bias term to conventional memory polynomials, improving linearization accuracy in low-power regime. Last, to improve the accuracy of coefficient derivation, Memory-Clustering Biased Memory Polynomial (MBMP) is proposed by grouping signals into clusters based on memory-attenuated input vectors and processing them with dedicated sub-models. It improves linearization accuracy in high-power regime. Experimental results demonstrate that the MBMP model reduces normalized mean square error (NMSE) by 16.12 dB, and reduces adjacent channel power ratio (ACPR) by about 12 dBm compared to conventional MP. Full article

Sex determination and differentiation in teleosts are governed by complex genetic regulatory networks that include evolutionarily conserved mechanisms. In this study, we investigated Boleophthalmus pectinirostris, a Gobiidae species lacking heterogametic sex chromosomes, using comparative gonadal transcriptome analysis to identify sex differentially expressed genes (DEGs). RNA sequencing of ovarian and testicular tissues identified 17,214 DEGs, including 14,302 upregulated in males and 2912 upregulated in females. These DEGs were primarily associated with male (e.g., dmrt1, amh, amhr2) or female (e.g., bmp15, gdf9, rspo1) sex determination and differentiation, steroidogenesis (e.g., hsd17b1, hsd3b1, cyp17a1), and meiosis (e.g., cyp26b1, aldh1a2, piwil2). Functional enrichment analysis revealed that male upregulated DEGs were involved in spermatogenesis pathways such as calcium signaling, while female upregulated DEGs were associated with oogenesis pathways including oocyte meiosis and progesterone-mediated oocyte maturation. Conserved regulators, notably dmrt1 and amh, were predicted to act as key hubs in protein–protein interaction networks, being primarily associated with reproductive processes and sex differentiation in B. pectinirostris. The amh gene produces two alternatively spliced isoforms that differ by a partial deletion in the second exon, both expressed in ovaries and testes. Collectively, this study provides the first comprehensive molecular framework of sex determination and differentiation in Gobiidae species, offering critical insights into the regulatory mechanisms of B. pectinirostris reproductive development. Full article

This study identified genomic regions associated with carcass traits and primal cut yields in Hanwoo cattle using weighted single-step genome-wide association study (WssGWAS). A total of 50,227 carcass records and genomic data from 23,573 animals with 45,057 single-nucleotide polymorphisms were analyzed. Heritability estimates were 0.24 for carcass weight, 0.22 for eye muscle area, 0.31 for backfat thickness, and 0.36 for marbling score, while those for primal cut yields ranged from 0.02 to 0.26. For carcass traits, candidate genes were identified for carcass weight (XKR4 2.35%, COBL 1.26%), eye muscle area (LCORL 1.56%, TGFBR2 1.49%), backfat thickness (ATG7 1.27%, MYPN 1.33%), and marbling score (TWIST2 1.16%, BMP4 1.14%). For primal cut yields, the chromosome 6 region containing WDR1 was commonly identified across six traits and the chromosome 4 region containing CACNA2D1 across five traits; the chromosome 28 region containing SIRT1 explained the highest genetic variance (6.46%) for striploin. These pleiotropic regions are potential targets for genomic selection to improve production efficiency and carcass value in Hanwoo. Full article