Frontiers in bioscience (Landmark edition)最新文献

Background: Lymphangiogenesis and phenotypic transformation of endothelial cells are closely associated with the progression of renal interstitial fibrosis. Inflammatory injury triggered by mineralocorticoid receptor (MR) activation serves as the initial stimulus for lymphangiogenesis.

Methods: Thirty specific pathogen-free (SPF) male C57BL/6 mice were assigned to three groups randomly: the control group (CON), aldosterone-treated group (ALD group, in which aldosterone was infused at a rate of 0.75 μg/h via mini-osmotic pumps for 12 weeks), and esaxerenone-treated group (ESA group, administered at a dosage of 1 mg/kg/day via diet). The expression levels of lymphatic markers (lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), vascular endothelial growth factor receptor 3 (VEGFR3), podoplanin, and VEGFC) were assessed using immunohistochemistry, immunofluorescence, and western blot analysis. Inflammatory injury markers (CD68, F4/80, IL-1β, TNF-α and TGF-β1) and endothelial-to-mesenchymal transition (EndMT, LYVE-1⁺ vimentin/α smooth muscle actin (α-SMA)⁺) were evaluated. In vitro, the effects of aldosterone on the migration, tube formation, and phenotypic transformation of human lymphatic endothelial cells (HLECs) in the presence of TGF-β1 or VEGFC were investigated.

Results: In the ALD group, significant increases in lymphangiogenesis, macrophage infiltration, and the expression of TGF-β1, TNF-α, IL-1β and VEGFC were observed. Immunofluorescence double staining revealed that VEGFC was predominantly secreted by macrophages, and that lymphatic endothelial cells exhibited expression of vimentin and α-SMA. In vitro experiments demonstrated that aldosterone promoted HLECs migration and tube formation, as well as the activation of inflammatory cytokines and MR. Flow cytometry analysis indicated that HLECs underwent myofibroblastic transformation, which could be attenuated by MR blocker esaxerenone.

Conclusions: Aldosterone induces inflammatory injury, thereby promoting renal lymphangiogenesis and EndMT.

Background: Temozolomide (TMZ) is a standard chemotherapeutic agent for glioma, but prolonged use frequently leads to drug resistance, reducing its therapeutic efficacy. Schisandrin B (Sch B), a lignan isolated from Schisandra chinensis, demonstrates promising anti-neoplastic activity. This study investigated the synergistic effects of Sch B and TMZ on U87 glioma cells to explore their combined influence on cell viability, apoptosis, and mitochondrial function.

Methods: U87 glioma cells were treated with Sch B, TMZ, or their combination. Cell viability was assessed using MTT assays. Apoptosis was evaluated by Hoechst staining and flow cytometry, while JC-1 staining and Western blotting were used to assess mitochondrial membrane potential, oxidative stress markers, and apoptosis-related proteins. Cell cycle analysis and pre-treatment with Z-VAD-FMK were performed to confirm pathway involvement.

Results: Combination treatment significantly reduced cell viability (54.14%) compared to TMZ (72.47%) or Sch B (70.4%) alone. Flow cytometry indicated elevated apoptosis (22.3%) in the combination group. JC-1 staining and protein expression analyses revealed mitochondrial depolarization, cytochrome c release, activation of caspase-3 and -9, and a decreased Bcl-2/Bax ratio. The combined treatment induced G2/M cell cycle arrest via p53/p21 activation and increased oxidative stress. Pre-treatment with Z-VAD-FMK partially reversed these effects, confirming caspase-dependent mitochondrial apoptosis.

Conclusions: Sch B enhances TMZ-induced cytotoxicity in U87 glioma cells by promoting mitochondrial dysfunction, oxidative stress, and caspase-mediated apoptosis. These findings suggest that Sch B may serve as a promising adjuvant to improve the efficacy of TMZ-based glioma therapy, warranting further validation in resistant and in-vivo models.

Background: The nucleotide "words" (k-mers) of the genome exhibit two essentially universal properties that follow probabilistically from the Conservation of Hartley-Shannon Information (CoHSI): (1) a Zipfian rank-ordered distribution of frequencies and (2) universal inverse symmetry. Here, we address the presence of these 2 properties in the transcriptome, a question of interest given the strong and specific structure/function constraints on RNAs, especially the protein-coding (CDS) sequences.

Methods: CDS and ncRNA (non-coding RNA) databases were accessed at e!Ensembl. For determination of a power-law, statistical tests of both necessity (linearity) and sufficiency (confidence that a power-law distribution could not be rejected) were applied. Compliance with inverse symmetry was assessed by linearity and residual standard error.

Results: The CDS and non-coding RNAs for 53 species were analyzed separately and the data presented as short movies. The results were consistent for all species analyzed, and taking the bonobo (Pan paniscus) as a representative species, the following results were obtained. For the Zipfian distribution of k-mer frequencies, statistically robust tests of both necessity (adjusted R-squared of 0.9932 and p ≤ 2.2 × 10^-16) and sufficiency were obtained for the CDS; for non-coding RNAs the test of necessity was robust (adjusted R-squared = 0.9982 and p ≤ 2.2 × 10^-16). Perturbations of inverse symmetry were observed in both CDS (slope = 0.91, adjusted R² = 0.77) and non-coding RNAs (slope = 1.02, adjusted R² = 0.84). The disruption of inverse symmetry in the CDS affected particularly the 3- and 6-mers and was shown to be associated with codon (especially stop codon) frequency in the open reading frame.

Conclusions: Whereas the CoHSI-predicted Zipfian distribution of k-mer frequencies was observed in both the protein-coding and non-coding RNAs of 53 species, in contrast the compliance with inverse symmetry was weaker. This weakening of compliance was seen to a greater extent in the CDS than in the non-coding portions of the transcriptome and may be associated with the necessity to maintain the integrity of the reading frame in the CDS. These results illustrate the general principle that local perturbations of an overall CoHSI-guided equilibrium state of a biological system can provide insight into the underlying causes of such perturbations.

Pericytes (PCs) are multifunctional mural cells embedded in the basement membrane of microvessels and play essential roles in the development and maintenance of the central nervous system. This review provides a comprehensive synthesis of the current knowledge on PC biology, tracing their trajectory from embryonic origins to specialized functions in the adult brain. During early brain development, PCs are recruited via platelet-derived growth factor B (PDGF-BB)/platelet-derived growth factor receptor beta (PDGFRβ) signaling and contribute to the formation of the blood-brain barrier (BBB), cortical architecture, and vascular stability. Their developmental plasticity is shaped by multiple embryonic origins and dynamic interactions with endothelial and neural precursor cells. In the adult central nervous system, PCs are central to maintaining BBB integrity, regulating cerebral blood flow, and modulating neurovascular coupling. They also participate in immune responses, metabolic waste clearance, and neuroprotection through the secretion of trophic factors and cytokines. Of particular interest is their emerging role in the expression of lipocalin-type prostaglandin D synthase (L-PGDS), which synthesizes prostaglandin D2-a molecule involved in sleep regulation, inflammation, and neurodegeneration. L-PGDS may also act as an amyloid β chaperone, implicating PCs in the pathology of Alzheimer's disease and other neurodegenerative disorders. The regulatory mechanisms of L-PGDS expression involve nuclear factor kappa B and Notch-Hes signaling, as well as potential modulation via brain-derived neurotrophic factor/tropomyosin receptor kinase B/protein kinase C pathway. By integrating developmental, molecular, and pathophysiological perspectives, this review positions PCs as key cellular regulators of brain function and highlights their potential as therapeutic targets in cerebrovascular and neurodegenerative diseases.

The important immunoregulatory roles of regulatory T cells (Tregs) include fostering tolerance to infections, controlling immune surveillance, and curtailing autoimmunity. Years of research have not only generated abundant knowledge in the field of Treg biology but also enabled the initial application of Tregs in cell therapy. However, most data in this field are obtained from laboratory animals and in vitro experiments. This review provides an updated summary and the latest understanding of Treg-targeting cell therapy. We introduce the unique traits of Tregs, review animal experiments and clinical trials on Treg injections, discuss limitations of Treg applications, and consider future perspectives on Treg-based therapies. Overall, the safety and potential efficacy of Tregs will broaden the scope of cell-based treatments.

Antibody-drug conjugates (ADCs) are an emerging class of cancer therapeutics comprised of a tumor-targeting antibody linked to a cytotoxic payload. Sacituzumab govitecan (SG or IMMU-132) is comprised of a trophoblast cell-surface antigen 2 (TROP-2)-directed antibody linked to the topoisomerase 1 inhibitor, SN-38. SG was designed to exploit the overexpression of TROP-2, observed in a variety of different epithelial cancers, to enhance tumor-selective cytotoxicity while minimizing damage to normal tissues. SG is approved for pretreated metastatic triple-negative breast cancer (mTNBC) and hormone receptor-positive human epidermal growth factor receptor 2 (HER2) negative breast cancer patients. While SG has shown significant clinical benefit, the objective response rate (ORR) observed with SG in pretreated mTNBC patients in the Phase I/II basket study was 33.3%, indicating a heterogeneous response profile to SG. This article explores the potential influence of autophagy, senescence, and the patient's immune system on the treatment response.

Background: Ultraviolet B (UVB) irradiation is a major environmental factor causing corneal epithelial cell apoptosis, leading to ocular surface damage and vision impairment.

Objective: This study aimed to investigate whether the standardized extract of Peucedanum japonicum Thunb. (SBP) protects corneal cells from UVB-induced apoptosis and explore its mitochondrial regulatory mechanisms.

Methods: Corneal epithelial cells were exposed to UVB irradiation, with or without treatment with SBP extract or its fractions. Nicotinamide adenine dinucleotide dehydrogenase activity, mitochondrial membrane potential, and mitochondrial morphology were assessed, and apoptosis-related proteins were analyzed using a cytokine antibody array kit. In vivo mouse models were also used to evaluate corneal damage following UVB exposure.

Results: The SBP extract, particularly the n-butanol (n-BuOH) fraction, significantly attenuated UVB-induced mitochondrial dysfunction and reduced apoptosis. Treatment restored mitochondrial membrane potential and improved corneal morphology in UVB-exposed mice. Chlorogenic acid, a major active compound, exhibited similar protective effects. The n-BuOH fraction demonstrated protective effects comparable to those of chlorogenic acid.

Conclusions: SBP protects corneal cells from UVB-induced apoptosis through mitochondrial stabilization, suggesting its potential as a therapeutic agent for ocular surface disorders.

The prevalence of male infertility attributed to oxidative stress (OS) is a growing concern globally. Traditional methods to treat male infertility have some limitations, including low efficacy and invasiveness. Additionally, assisted reproductive procedures, such as in vitro fertilization and intracytoplasmic sperm injection, are expensive and carry higher risks. These challenges underscore the need for innovative solutions. A multidisciplinary approach is imperative, drawing insights from fields such as reproductive biology, nanotechnology, and clinical research to effectively combat male infertility caused by OS. Recent advancements in nanobiotechnology provide a promising opportunity to tackle male infertility caused by OS. These advancements enable the design and development of nanoantioxidants (nanoAOXs) and drug delivery systems tailored to the male reproductive environment. This review highlights the recent progress in the rational design of nanomaterials, with a specific focus on nanoAOXs for managing male infertility associated with OS.

Objective: This study investigated necroptosis-related molecular alterations in the endometrium of patients with polycystic ovary syndrome (PCOS) using quantitative proteomic analysis and developed a predictive model for pregnancy outcomes based on these findings.

Methods: Liquid chromatography-tandem mass spectrometry was used to identify and quantify endometrial proteins. Differentially expressed proteins (DEPs) were screened and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to identify key pathways. Candidate prognostic necroptosis-related proteins were obtained by intersecting DEPs with the necroptosis gene set, followed by univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses to select those associated with pregnancy outcomes and construct a predictive model.

Results: A total of 611 DEPs were identified (132 upregulated and 479 downregulated). KEGG enrichment revealed significant involvement of the necroptosis pathway. Six necroptosis-related proteins were identified using Cox and LASSO regression analyses and used to construct the predictive model. Kaplan-Meier analysis showed that the low-risk group had significantly better pregnancy outcomes than the high-risk group. The model achieved an area under the receiver operating characteristic curve of 0.903 for predicting live birth at 37 weeks, and decision curve analysis demonstrated superior clinical benefit compared to conventional clinical indicators. Furthermore, correlation analysis revealed significant associations between necroptosis-related proteins and classical endometrial receptivity markers, suggesting potential molecular crosstalk.

Conclusion: Proteomic profiling revealed enrichment of the necroptosis pathway in the endometrium of patients with PCOS. The constructed model indicated preliminary predictive potential for pregnancy outcomes, suggesting that necroptosis may contribute to impaired endometrial receptivity.

Background: In contemporary gene therapy research, recombinant adeno-associated virus (rAAV) has emerged as a pivotal delivery vehicle due to its favorable safety profile and capacity for sustained transgene expression. The most commonly utilized rAAV variants are hybrid vectors constructed by packaging the AAV2 genome within the capsid proteins of alternative serotypes (e.g., AAV1, AAV5, AAV8, or AAV9). This chimeric design combines the stable genomic integration and long-term expression characteristics inherent to AAV2 with the distinct tissue tropisms conferred by different capsid serotypes. Consequently, these engineered rAAVs exhibit enhanced organ-targeting specificity, enabling more efficient and selective gene delivery to desired tissues while minimizing off-target effects.

Methods: To identify the optimal hybrid vector for germ cell-directed gene delivery in mice, ten distinct chimeric AAV variants were generated by pseudotyping the AAV2 genome with diverse capsid proteins, followed by microinjection into seminiferous tubules via the efferent ducts. Transduction efficiency was comparatively evaluated at 4 weeks post-injection.

Results: We demonstrated that AAV2/9 mediated robust and widespread enhanced green fluorescent protein (EGFP) expression in the mouse testis. Through immunofluorescence assays, we demonstrated that AAV2/9 demonstrated the capability to express in nearly all testicular cells, with remarkable efficiency and durability.

Conclusions: AAV2/9 demonstrated superior efficacy as a gene delivery vector for murine testicular germ cells without observable adverse effects on testicular development or spermatogenesis. This favorable safety profile, combined with high transduction efficiency establishes AAV2/9 as a promising candidate for therapeutic gene transfer to testicular germ cells. Collectively, our study identifies AAV2/9 as a premier vector for germ cell-directed gene therapy, providing crucial preclinical evidence to inform capsid selection for treating male infertility.