Biomolecules最新文献

Mesenchymal stem/stromal cells (MSCs) exhibit broad differentiation capability and strong immunoregulatory potential mediated through intercellular communication and the release of diverse paracrine mediators. They represent a promising but still investigational therapeutic approach for managing complications associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). This review provides an updated synthesis of MSC biology, their bidirectional interaction with immune cells, and their functional contribution to the hematopoietic niche. It also evaluates current clinical evidence regarding the therapeutic roles of MSCs and MSC-derived extracellular vesicles (EVs) in acute and chronic graft-versus-host disease (aGVHD/cGVHD), as well as in poor graft function. Mechanistic insights encompass macrophage polarization toward an anti-inflammatory phenotype, inhibition of dendritic cell maturation, enhancement of regulatory T-cell expansion, and modulation of cytokine signaling pathways. Within the bone marrow milieu, MSCs contribute to stromal restoration and angiogenic repair. Recent phase II/III trials in steroid-refractory (SR)-aGVHD have demonstrated overall response rates ranging from 48 to 71%. Efficacy appears particularly enhanced in pediatric patients and with early MSC administration. Across studies, MSC therapy shows a favorable safety profile; however, heterogeneity in response and inconsistent survival outcomes remain notable limitations. For poor graft function, limited prospective studies indicate hematopoietic recovery following third-party MSC infusions, and combination approaches such as co-administration with thrombopoietin receptor agonists are under investigation. MSC-derived EVs emulate many immunomodulatory effects of their parental cells with a potentially safer profile, though clinical validation remains in its infancy. MSC-oriented interventions hold substantial biological and therapeutic promise, offering a favorable safety margin; however, clinical translation is hindered by product variability, suboptimal engraftment and persistence, and inconsistent efficacy across studies. Future directions should emphasize standardized manufacturing and potency assays, biomarker-driven patient and timing selection, optimized conditioning and dosing strategies, and the systematic appraisal of EV-based or genetically modified MSC products through controlled trials.

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.

Drug-resistant bacteria cause millions of global infections each year, and the development of alternative antimicrobial drugs has become a serious undertaking. Currently, peptides with antimicrobial activity represent potential candidates for new antibiotic discovery as they are less likely to cause drug resistance in bacteria. In this study, bifunctional peptides with potent trypsin-inhibitory activity and antimicrobial activity were obtained by rational computation-based structural modifications to a novel Bowman-Birk-type inhibitor (BBI) peptide. The analogues not only displayed potent bacterial killing ability against two drug-resistant bacteria strains of E. coli but also an excellent safety profile, as assessed by low haemolytic activity and low anti-proliferation activity on HaCaT cells. Throughout the molecular dynamics simulations, the peptides exhibited stable adsorption onto the mixed POPE/POPG membrane; most amino acid residues of the AMPs remained bound to the membrane surface, with a few amino acid residues partially penetrating the membrane interior. This showed that the electrostatic interactions were the dominant driving force mediating the peptide-membrane associations. In addition, the tested peptides displayed a degree of stability in the presence of salt ions, serum, and trypsin. These modified peptides thus possess potential as clinical antibacterial agents, and the strategies used in structural modification may also provide a different path to developing new antimicrobial peptides.

Currently, the increased incidence of invasive fungal infections globally is posing a significant challenge to public health. Due to drug resistance issues, the clinical efficacy of existing antifungal drugs is seriously insufficient, while new drug development progresses slowly. Consequently, there is an urgent need to discover and develop novel antifungal therapeutics. Natural products have the characteristics of wide sources and few adverse reactions and are one of the sources for developing antifungal drugs. Numerous studies have shown that many compounds isolated from plants and traditional Chinese medicine have antifungal activity and diverse antifungal mechanisms. Thymol, a monoterpene phenol compound from thyme (Lamiaceae), has multiple biological functions such as antibacterial, antioxidant, and anti-inflammatory. Recent research has found that thymol has strong antifungal activity, and its molecular mechanisms involve cell membrane rupture, interference with cell wall synthesis, disruption of mitochondrial function and energy metabolism, inhibition of biofilm, inhibition of virulence factor expression, inhibition of key enzymes, and induction of cell apoptosis. This review aimed to summarize the antifungal activity of thymol and the underlying molecular mechanisms, safety, and potential clinical applications. Emerging technologies in thymol delivery systems and future research directions are also discussed. The comprehensive analysis aims to provide a detailed understanding of fungal infections and the role of thymol in antifungal treatment, offering insights for further research and clinical practice.

Acute pancreatitis (AP) is a severe inflammatory disorder characterized by a complex molecular pathophysiology involving premature zymogen activation, organelle dysfunction, and systemic immune dysregulation. Current therapeutic strategies remain largely supportive, underscoring the critical need for specific molecular-targeted interventions. Baicalein, a bioactive flavonoid derived from Scutellaria baicalensis Georgi, has emerged as a potent pleiotropic agent. This review comprehensively synthesizes the molecular mechanisms underlying baicalein's therapeutic efficacy in AP. Its capacity to intercept the pathological cascade at multiple checkpoints is elucidated, from mitigating the initiating cytosolic calcium overload and preserving mitochondrial integrity to suppressing the cytokine storm via the TLR4/NF-κB/MAPK signaling axis. Crucially, baicalein modulates the pancreatic immune microenvironment by driving the phenotypic polarization of macrophages from pro-inflammatory M1 to reparative M2 states and regulating neutrophil dynamics, specifically by inhibiting infiltration and neutrophil extracellular trap formation. Furthermore, its role in orchestrating regulated cell death pathways is highlighted, specifically by blocking pyroptosis and ferroptosis while modulating apoptosis, and its function as a biophysical scavenger of circulating histones and pancreatic lipase to neutralize systemic toxins. Consequently, this review emphasizes the multi-target biological activities of baicalein, providing a mechanistic rationale for its development as a precision therapeutic candidate for AP.

Adherent-invasive E. coli (AIEC) is closely related to inflammatory bowel disease (IBD). However, its pathogenic mechanism has not yet been fully elucidated. Using a BLASTP search, we discovered that the amino acid sequence of a putative protein (UFP37798.1) in the AIEC LF82 strain is highly homologous to some regulators in the SlyA family. We named it EruA. We displayed the secondary structures of EruA using bioinformatics, overexpressed the His₆-tagged EruA protein using SDS-PAGE, and dissected the genetic organization of the eruA chromosomal region using 5'RACE. We constructed an eruA deletion mutant (ΔeruA) and a complementary strain (CΔeruA) of the LF82 strain. The transcriptomes of wild-type (WT) and ΔeruA bacteria were compared using RNA sequencing and qRT-PCR, thereby identifying 32 differentially expressed genes (DEGs). Based on YASARA software and EMSA analysis, EruA directly binds to the consensus sequences (P_fimA and P_tnaB) in the promoter region of the fimA and tnaB genes from these DEGs. By using a super-resolution confocal microscope (SCM), counting CFUs of colonies on plates, indole quantification, and crystal violet staining of biofilms adhered to tubes or 96-well plates, we found that EruA activates the fimA to promote bacterial adhesion to intestinal epithelial cells and activates the tnaB to enhance bacterial indole production and biofilm formation. Moreover, EruA helps AIEC resist environmental stress and enhances bacterial survival within macrophages as well as loading in mouse tissues. Notably, EruA promotes AIEC colonization in the colons of mice and exacerbates intestinal inflammation caused by bacterial infection in mice with DSS-induced inflammatory colitis, manifested by weight loss, colon length shortening, and pathological changes in colon tissues. Therefore, EruA plays a key role in the pathogenicity of AIEC.

Polyunsaturated fatty acids (PUFAs), particularly omega-3 derivatives such as docosahexaenoic acid (DHA), are precursors of specialized pro-resolving mediators (SPMs) that actively orchestrate the resolution of inflammation. Among these, maresins (MaRs) have gathered increasing attention due to their potent immunomodulatory and tissue-regenerative properties. This review provides a comprehensive synthesis of the current knowledge on the biosynthesis, structural diversity, and biological functions of MaRs, with a focus on MaR1. We discuss the enzymatic pathways involved in the generation of MaR1, MaR2, MaRs conjugates in tissue regeneration (MCTRs), and maresin-like lipid mediators (MaR-Ls), highlighting their roles in modulating inflammatory responses, promoting phagocytosis, and restoring tissue homeostasis. Preclinical evidence from in vitro and in vivo models demonstrates that MaRs exert protective effects in a wide range of pathological contexts, including neuroinflammation, liver injury, cardiovascular dysfunction, pulmonary diseases, and metabolic disorders. Although their therapeutic promise is well-supported, key gaps remain in the understanding of MaRs biosynthesis, receptor specificity, and translational applicability. This review emphasizes the importance of advancing mechanistic and clinical research to fully harness MaRs as part of next-generation therapeutics in inflammation-driven diseases.

The p53 tumor suppressor, a key transcription factor, acts as a cellular stress sensor that regulates hundreds of genes involved in responses to DNA damage, oxidative stress, and ischemia. Through these actions, p53 can arrest cell cycle, initiate DNA repair, or trigger cell death. In addition to its nuclear functions, p53 can translocate to mitochondria to promote apoptosis. Studies using isolated mitochondria have suggested that p53 drives the voltage-dependent anion channel (VDAC1) into high molecular mass complexes to mediate apoptosis. VDAC1 is a central regulator of cellular energy production and metabolism and also an essential player in apoptosis, induced by various apoptotic stimuli and stress conditions. We previously demonstrated that VDAC1 oligomerization, induced by various apoptosis stimuli and stress conditions, forms a large pore that enables cytochrome c release from mitochondria, thereby promoting apoptotic cell death. In this study, we show that p53 interacts with VDAC1, modulates its expression levels, and promotes VDAC1 oligomerization-dependent apoptosis. Using purified proteins, we found that p53 directly binds VDAC1, as revealed by microscale thermophoresis and by experiments using bilayer-reconstituted VDAC1, in which p53 reduced VDAC1 channel conductance. Furthermore, overexpression of p53 in p53-null cells or in cells expressing wild-type p53 increased VDAC1 expression and induced VDAC1 oligomerization even in the absence of apoptotic stimuli. Together, these findings identify VDAC1 as a direct p53 target whose expression, oligomerization, and pro-apoptotic activity are regulated by p53. They also reinforce the central role of VDAC1 oligomerization in apoptosis.

Smart nanocarriers are being increasingly explored to improve the performance selectivity of cancer chemotherapy. Here, two pH-responsive magnetic nanocarriers were developed using quaternary chitosan (HTCC) functionalized with 3-(triethoxysilyl)propyl isocyanate- ICPTES (MNP-HTCC1) or 3-(glycidyloxypropyl)trimethoxysilane-GPTMS (MNP-HTCC2) to form hybrid silica shells on Fe₃O₄ cores. The resulting core-shell nanoparticles (14.5 and 12.5 nm) displayed highly positive zeta potentials (+45.4 to +27.1 mV, pH 4.2-9.5), confirming successful HTCC incorporation and strong colloidal stability. Both nanocarriers achieved high doxorubicin (DOX) loading at pH 9.5, reaching 90% efficiency and a capacity of 154 µg DOX per mg. DOX release was pH-dependent, with faster release under acidic conditions relevant to tumor and endo-lysosomal environments. At pH 4.2, MNP-HTCC1 released 90% of DOX over 72 h, while MNP-HTCC2 released 79%. Release at pH 5.0 was intermediate (67-72%), and moderate at physiological pH (43-55%). All formulations showed an initial burst followed by sustained release. Kinetic modelling (Weibull) indicated a diffusion-controlled mechanism consistent with Fickian transport through the HTCC-silica matrix. Cytotoxicity assays using MCF-7 breast cancer cells revealed greater cytotoxicity for DOX-loaded nanocarriers compared with free DOX, with MNP-HTCC1 showing the strongest effect. Overall, these HTCC-based magnetic nanocarriers offer efficient loading, controlled pH-triggered DOX release, and enhanced therapeutic performance.

Bladder discomfort, urgency, and frequency of urination are the hallmarks of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic illness. Although the precise etiology remains unclear, numerous clinical investigations have established inflammation as a pivotal factor in its pathogenesis, encompassing uroepithelial damage, mast cell activation, and neuroinflammatory responses. This review delineates the pathological features and classification of IC/BPS, emphasizing the contribution of inflammatory mechanisms and the involvement of cytokines as key mediators in disease progression. The insights presented aim to guide the advancement of innovative treatment approaches.