Neural networks are found to play an important role in monitoring and coordinating cardiac physiological activities. However, the clinical use of neuroregulatory strategies for repairing infarcted myocardium, such as vagus nerve stimulation and pharmacological activation, confronts the challenges of managing stimulation signals and potential drug side effects. In this study, an innovative myocardial infarction repair strategy by creating a "pre-neuralized" scaffold that combines strontium silicate microparticles with neural stem cells (NSCs) is introduced. Strontium silicate promotes NSCs differentiation, resulting in a scaffold enriched with mature neurons. This scaffold exhibits neuroregulatory capabilities that enhance the maturation and synchronized contraction of cardiomyocytes, facilitating myocardial repair and improving cardiac function in vivo. The findings indicate that the pre-neuralized scaffold aids myocardial recovery by modulating genes linked to circadian rhythm, underscoring the strategic benefit of neural-induced regulation in tissue repair. In conclusion, this study presents a promising approach to repairing infarcted myocardium using inorganic biomaterial-induced scaffolds with neuromodulatory properties from the perspective of systemically physiological regulation. This work may offer a new perspective for addressing complex tissue and organ injuries.

Embryo implantation is a critical step at the beginning of pregnancy, occurring during a specific and limited period known as the "implantation window". Successful implantation involves various signaling pathways and molecular interactions. Recent studies have highlighted the importance of extracellular vesicles (EVs) in mediating these complex interactions. Different cell types release EVs to transfer signals to other cells or tissues. Additionally, emerging evidence suggests that EVs regulate signaling between the developing embryo and endometrium. In this review, we summarize current findings that highlight the role of EVs in the reproductive tract, gamete production, and their potential roles in embryo development and implantation. We then examine studies emphasizing the role of EVs in embryo-maternal interactions and implantation. Finally, we will explore the theranostic potential of EVs in various aspects of assisted reproductive technology (ART), including modulation of embryo-maternal interactions, enhancement of embryo quality, and improvement of endometrial receptivity. A more comprehensive understanding of EVs in the pathology of recurrent implantation failure could support the development of personalized treatments.

Pterostilbene (PT), a natural dimethoxy analogue of resveratrol, exhibits enhanced bioavailability and lipophilicity, making it a more effective therapeutic candidate than resveratrol. These pharmacokinetic advantages improve its cellular uptake and metabolic stability, positioning PT as a promising compound in cancer treatment. PT has shown significant anticancer activity in several malignancies, including melanoma, breast, colorectal, and ovarian cancers. Its mechanisms of action include induction of apoptosis through caspase activation, cell cycle arrest, and inhibition of angiogenesis and metastasis via downregulation of matrix metalloproteinase-9 and vascular endothelial growth factor. PT also modulates epigenetic processes such as DNA methylation and histone modifications, and targets cancer stem cells by reducing the expression of stemness markers like CD44 and c-Myc. Additionally, PT enhances the efficacy of standard chemotherapeutic agents such as cisplatin, doxorubicin, and 5-fluorouracil, with preclinical studies showing synergistic effects and reversal of drug resistance. A Phase II clinical trial (NCT03671811) in endometrial cancer patients has confirmed the safety of PT and revealed its ability to modulate immune-related gene expression and suppress mechanistic target of rapamycin (mTOR) signaling. Despite promising results, several challenges remain particularly low water solubility, limited systemic bioavailability, lack of large-scale human studies, and undefined therapeutic protocols. Future research should focus on advanced formulation strategies, rigorous clinical trials across cancer types, and identification of patient-specific therapeutic responses to support PT's integration into oncology practice.

Liver diseases, such as hepatitis, cirrhosis, and liver cancer, pose significant public health challenges, ranking as the twelfth leading cause of death globally. Given the liver's critical functions in metabolism, detoxification, and biosynthesis, its impairment can lead to severe consequences, often resulting in end-stage liver failure. Although liver transplantation is regarded as the definitive intervention for advanced liver disease, factors such as a shortage of donors and potential surgical complications necessitate the investigation of non-surgical regenerative medicine alternatives. This manuscript provides a comprehensive review of innovative non-surgical therapies aimed at liver regeneration, with an emphasis on both cell-based and cell-free approaches. It examines the contributions of various stem cell populations, including mesenchymal stem cells, hematopoietic stem cells, and induced pluripotent stem cells, in facilitating liver repair through mechanisms of differentiation and paracrine signaling. Furthermore, it explores the therapeutic potential of exosomes and conditioned media derived from stem cells as biotherapeutic agents in the context of regenerative medicine. By elucidating the mechanisms that underpin liver regeneration, this study aspires to inform the development of effective therapeutic strategies to address liver diseases and slow their progression. By elucidating the underlying mechanisms of liver regeneration, this study aims to contribute to the development of effective therapeutic strategies to address liver diseases and slow their progression.

Mesenchymal stem cells (MSCs) have emerged as a promising option for gene and cell therapy due to their unique biological properties. MSC-based cell therapies have garnered significant attention for various clinical applications; however, repeated administrations are often necessary to achieve sustained therapeutic effects. Genetic modification techniques have enhanced MSCs' intrinsic capabilities, improving their therapeutic efficacy in both experimental and clinical settings. Key functional properties anti-inflammatory, anti-fibrotic, survival, and migratory capacities have become central targets for genetic enhancement. Numerous studies have explored the genetic modification of MSCs to address overcoming the transient nature of their therapeutic effects. Notably, the safety of genetically engineered MSCs remains a critical concern in preclinical and clinical investigations.In this review, we summarize current strategies for the genetic modification of MSCs and discuss recent findings on their application in animal disease models.

NUMB is a tumor suppressor gene that functions by inhibiting the action of the NOTCH proto-oncogene and enhancing the levels and activity of the tumor suppressor protein p53. In breast cancer (BC), NUMB loss of function (LOF), mediated by various molecular mechanisms, is a frequent and causal event. Herein, it is established that loss of NUMB protein, resulting from protein hyper-degradation, is the prevalent mechanism of NUMB LOF in BC. Through an RNAi-based screening, the CRL7FBXW8 complex is identified as the E3 ligase complex responsible for NUMB hyper-degradation in BC. Genetic and pharmacological inhibition of CRL7FBXW8 rescues the transformation-related phenotypes induced by NUMB LOF in BC cell lines and in patient-derived xenografts. These effects are directly dependent on the restoration of NUMB protein levels. Thus, enhanced CRL7FBXW8 activity, through its interference with the tumor suppressor activity of NUMB, is a causal alteration in BC, suggesting it as a potential therapeutic target for precision medicine.

The complexity and precision of the human nervous system have posed significant challenges for researchers seeking suitable models to elucidate refractory neural disorders. Traditional approaches, including monolayer cell cultures and animal models, often fail to replicate the intricacies of human neural tissue. The advent of organoid technology derived from stem cells has addressed many of these limitations, providing highly representative platforms for studying the structure and function of the human embryonic brain and spinal cord. Researchers have induced neural organoids with regional characteristics by mimicking morphogen gradients in neural development. Recent advancements have demonstrated the utility of neural organoids in disease modeling, offering insights into the pathophysiology of various neural disorders, as well as in the field of neural regeneration. Developmental defects in neural organoids due to the lack of microglia or vascular systems are addressed. In addition to induction methods, microfluidics is used to simulate the dynamic physiological environment; bio-manufacturing technologies are employed to regulate physical signaling and shape the structure of complex organs. These technologies further expand the construction strategies and application scope of neural organoids. With the emergence of new material paradigms and advances in AI, new possibilities in the realm of neural organoids are witnessed.

Cisplatin-induced ototoxicity remains a clinical dilemma with limited mechanistic understanding and no food and drug administration (FDA)-approved therapies. Despite emerging roles of small extracellular vesicles (sEV) in drug ototoxicity, their molecular cargo profiles and causal roles to cisplatin-induced ototoxicity are unexplored. This study systematically investigates sEV derived from cochlear explants treated with cisplatin (Cis-sEV) and controls (Ctrl-sEV) using multi-omics profiling. Through small RNA sequencing, 83 differentially expressed microRNAs (miRNAs) are identified in Cis-sEV compared to Ctrl-sEV. Notably, mmu-miR-34a-5p, mmu-miR-140-5p, mmu-miR-15b-5p, mmu-miR-25-3p, and mmu-miR-339-5p are significantly upregulation in Cis-sEVs. Predicted target pathways of these differentially expressed miRNAs are enriched in apoptosis, inflammation, and cellular damage, indicating their potential involvement in cisplatin-induced cochlear damage. LC-MS/MS analysis reveals 90 upregulated and 150 downregulated proteins in Cis-sEV, with many involved in damage response. Specifically, CLTC, CCT2, ANXA6, and HSPA8 are uniquely upregulated proteins in Cis-sEV, and CLTC and ANXA6 are exclusively co-localized in hair cells (HCs) post-cisplatin exposure, suggesting that Cis-sEV originate primarily from damaged HCs. Moreover, CLTC in sEV may serve as a potential biomarker for cisplatin-induced ototoxicity as verified in both in vitro and in vivo models. This study provides novel insights into the molecular mechanisms of cisplatin-induced ototoxicity and identifies potential biomarker and therapeutic targets.

In this study, we fabricated composite scaffolds containing micro-fibrillated cellulose (MFC), chitosan (CS), and hydroxyapatite (HAp) were fabricated using the freeze-drying technique. N-Boc-L-cysteine methyl ester (NBLCME) was synthesized and incorporated into the composite scaffold (CS/MFC/HAp) at different concentrations (20-100µg/ml). The composite scaffolds were characterized by SEM and FTIR results. Interconnected porous structure showed that the scaffolds had 80-90% porosity with a pore diameter range of 100-450µm and fiber lengths of 6.1 -11.87 µm. FTIR analysis confirmed the interaction between CS/MFC/HAp and NBLCME. The treated scaffolds exhibited sustained drug delivery following Fickian diffusion behavior (n ≤ 0.45). The biological study of treated scaffolds on human osteosarcoma cells (MG63 cell line) was evaluated by examining cell viability, ALP, ARS activities, and cell adhesion. The cytotoxicity of the treated scaffolds showed no cytotoxic effects on the MG63 cell line. ALP and ARS activities showed significantly enhanced phosphate and calcium deposition on the scaffold. Taken together, the result suggested that the fabricated composite scaffold (CS/MFC/HAp) incorporated with NBLCME showed excellent properties and its potential for bone-related applications.

The major objective of the present study is to develop and evaluate phenyl boronic acid (PBA) conjugated solid lipid nanoparticles (PBA-SUL@SLN) for the targeted delivery of sulindac (SUL) to breast cancer (BC) cells.Significance: Utilizing a dual approach that combines PBA-mediated targeting with Notch-1 pathway inhibition by SUL, the study aims to enhance therapeutic selectivity and efficacy against an aggressive BC subtype, triple negative breast cancer (TNBC), which lacks well defined molecular targets.

Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the aging-related clonal expansion of preleukemic mutations in hematopoietic stem cells. While CHIP has been studied in cardiometabolic diseases (CMDs), its role in the long-term progression from the absence of CMD to the development of a single CMD, cardiometabolic multimorbidity (CMM), and eventual mortality remains uncertain. This study aimed to investigate the association between CHIP and gene-specific CHIP subtypes with the progression of CMD transitions.

Bone marrow adipose tissue (BMAT) plays an essential role in skeletal health and systemic metabolism, particularly under conditions of ageing and osteoporosis. Despite increasing recognition of BMAT as an active endocrine organ, the molecular mechanisms underlying its formation and expansion remain incompletely understood.

Injectable platelet-rich fibrin (I-PRF) is an autologous fibrin matrix rich in leucocytes, platelets and growth factors, and could serve as a sustained-release vehicle for a variety of active biomolecules. The aim of the current randomized controlled trial was to compare the effect of vitamin C (VitC) with I-PRF as a locally delivered adjunct to professional mechanical plaque removal (PMPR) versus PMPR with local delivery of I-PRF or PMPR alone on non-surgical periodontal treatment (NSPT) outcomes of stage-II periodontitis.

Congenital ptosis, a genetic disorder involving levator palpebrae muscle dysfunction, is often associated with congenital myopathy. The genetic causes of this condition remain poorly understood. In this study, we identified FOXK2 mutations in five pedigrees with congenital myopathy and ptosis through whole exome sequencing and Sanger sequencing. Zebrafish with foxk2 deficiency exhibited underdeveloped skeletal muscles and reduced mobility, while mice with Foxk2 deletion in skeletal muscle stem cells (MuSCs) showed generalized skeletal muscle abnormalities. Further analysis revealed that FOXK2 deficiency impaired myogenic differentiation in C2C12 cells and disrupted mitochondrial homeostasis in both mouse MuSCs and C2C12 cells. Rescue experiments confirmed the loss-of-function effects of FOXK2 mutation. Coenzyme Q10 treatment improved mitochondrial function and alleviated skeletal muscle development defects in Foxk2-deficient mice. Preliminary omics analysis suggested FOXK2 directly regulates the expression of mitochondrial function-related genes by modulating chromatin accessibility at its binding sites. Our study identifies FOXK2 as a novel pathogenic gene for congenital myopathy with ptosis and highlights its essential role in skeletal muscle development and mitochondrial homeostasis, offering insights for potential diagnostics and therapies.

During aging, hematopoietic stem cell (HSC) function progressively declines which can lead to reduced blood cell production and regeneration. This work uncovered that cell surface presentation of P-selectin (CD62P, encoded by Selp) increases in a large fraction of aging HSCs driven by a proinflammatory milieu in mice. Notably, expression of P-selectin molecularly and functionally dichotomized the aging HSC pool; stem cells presenting with highly abundant P-selectin were hallmarked by aging-associated gene expression programs and reduced repopulation capacity upon regenerative stress. Ectopic expression of Selp in young HSCs was sufficient to impair long-term reconstitution potential and impair erythropoiesis. Mechanistically, we uncovered that P-selectin receptor activation by its primary ligand, P-selectin glycoprotein ligand-1, suppressed aging-associated gene expression, and, reversely, lack of P-selectin signaling led to HSC premature aging. Collectively, our study uncovered a functional role of P-selectin engagement in regulating HSC regeneration and driving stem cell aging when perturbed.

Intestinal fibrosis represents a clinically intractable complication in colitis management. This study elucidates the regulatory mechanisms by which bone mesenchymal stem cell-derived exosomes (BMSC-Exo) modulate the myofibroblastic transdifferentiation of intestinal fibroblast. BMSC-Exo was isolated and characterized. RNA sequencing was performed on TGF-β-activated CCD-18Co fibroblasts following BMSC-Exo intervention. Histopathology, immunoblotting, migration assays, and imaging techniques (immunofluorescence/immunohistochemistry) were employed to quantify extracellular matrix (ECM) deposition and fibrotic responses in both in vitro and murine models. Human colonic specimens from Crohn's disease (CD) patients with structuring complications were analyzed for fibrotic components. BMSC-Exo was successfully isolated. BMSC-Exo treatment significantly attenuated fibroblast activation and migratory capacity, concomitant with downregulating collagen I and N-cadherin expression. In vivo, histological fibrosis score, collagen deposition, and α-SMA expression were significantly decreased after BMSC-Exo administration. Transcriptomic profiling revealed significant enrichment of ECM remodeling pathways following BMSC-Exo intervention, with connective tissue growth factor (CCN2) identified as a pivotal mediator. Functional validation through CCN2 overexpression demonstrated the mechanistic dependence of BMSC-Exo's anti-fibrotic effects on the CCN2-TGF-β axis. Clinical specimens revealed a marked increase in collagen fiber deposition and co-upregulation of CCN2 in stenotic CD tissues compared to non-strictured regions. BMSC-Exo exerts potent anti-fibrotic effects through the suppression of fibroblast differentiation, mediated by targeted inhibition of the CCN2-TGF-β signaling nexus. These findings establish exosome-based therapy as a novel therapeutic strategy for intestinal fibrosis.

Radio-resistance of cancer stem-like cells (CSCs) is associated with the failure of radiation therapy. ZsGreen1-positive (ZsG⁺) cells, which exhibit low proteasome activity, have been used to enable the detection and isolation of CSCs. However, the mechanisms of radio-resistance in canine tumor cells with low proteasome activity remain unclear. This study aimed to elucidate the radio-resistance mechanisms of ZsG+ cells by identifying a potential target of canine CSCs. ZsG+ cells, isolated using flow cytometric cell sorting, were compared with ZsG- cells. Sulfasalazine was used to suppress glutathione (GSH) synthesis by inhibiting xCT. In vitro experiments demonstrated a significantly higher radio-resistance in ZsG+ cells than in ZsG- cells. After X-irradiation, ZsG+ cells had fewer p53‑binding protein 1 (53BP1) foci, low reactive oxygen species (ROS) accumulation, and high GSH content. Sulfasalazine caused radiosensitization of ZsG+ cells with an increased number of 53BP1 foci by decreasing GSH contents and increasing ROS accumulation. The low proteasome activity played a role in xCT upregulation. In conclusion, canine tumor cells with low proteasome activity are radio-resistant due to high GSH content and low ROS accumulation. Sulfasalazine causes radiosensitization of the tumor cells by altering redox balance by inhibiting GSH synthesis for effective targeting of canine CSCs.

Biallelic mutations in the DCPS gene disrupting the decapping activity of the scavenger decapping protein DcpS, leads to neurodevelopmental deficiencies and intellectual disability. However, the molecular basis for the neurogenesis defects in these individuals remains unknown. Here we show that cells derived from individuals with a DCPS mutation harbor a creatine deficiency and a corresponding elevation of the creatine precursor, guanidinoacetate (GAA). The altered metabolite levels are a consequence of a reduction in both the mRNA and protein levels for the enzyme that converts GAA into creatine, guanidinoacetate methyltransferase. Importantly, the compromised neurogenesis and neurite outgrowth phenotypes observed during the differentiation of DcpS mutant patient derived induced pluripotent stem cells into neurons was reversed upon supplementation of creatine monohydrate. These findings suggest creatine deficiency as an underlying factor for the neurogenetic defect detected in DcpS mutant cells and a potential driver of the neurological deficiencies in affected individuals.

Recent research underscores the crucial role of hormone regulation in benign prostatic hyperplasia (BPH) and the therapeutic promise of growth hormone-releasing hormone (GH-RH) antagonists. BPH incidence in aging men doubled over three decades, driven by prostatic enlargement and lower urinary tract symptoms (LUTS). Aging-related changes in GH-RH and luteinizing hormone-releasing hormone (LH-RH) biology promote BPH through hormonal and inflammatory processes. Traditional therapies provide symptomatic relief but often fail to prevent progression. This review explores the 50-year extensive development of LH-RH and GH-RH peptide analogs from discovery to delivery and their potential in BPH treatment. In preclinical studies, GH-RH antagonists reduced prostate volume, improved LUTS, and modulated inflammation mediated by NF-κB and IGF-I. Clinical trials are needed to validate antagonist efficacy and safety. Given BPH's public health impact among the aged, and especially among aging Veterans, integrating GH-RH antagonists into management strategies may offer precision-based therapeutic advancements.