Bioscience trends最新文献

Photoaging is a distinct form of pathological skin aging driven primarily by chronic ultraviolet (UV) radiation, which clinically manifests as wrinkles, dyspigmentation, and loss of elasticity. Although core molecular events induced by UV-such as oxidative stress and DNA damage-are relatively well-understood, there is still a lack of a systematic and integrated understanding of how diverse cell types in the skin collectively drive photoaging through complex interactive networks. This review systematically elaborates the cellular and molecular mechanisms underlying skin photoaging. The key pathways involved are examined, including oxidative stress, apoptosis, dysregulated autophagy, activation of inflammatory cascades, and degradation of the extracellular matrix (ECM). This review further details the pivotal roles of and reciprocal crosstalk among fibroblasts, keratinocytes, melanocytes, and various immune cells. By providing an integrated perspective on these interactions, this review outlines the cellular and molecular mechanism of UV-associated senescence, which uniquely integrates the roles of the immune microenvironment and cellular crosstalk, providing a roadmap for next-generation anti-photoaging strategies.

SLC26A4 is a major causative gene for hereditary hearing loss, its mutation spectrum shows pronounced population specificity. In Chinese populations, patients predominantly carry biallelic mutations, and compound heterozygous genotypes are prevalent, which results in a wide spectrum of auditory phenotypes. However, how different alleles interact within these contexts to shape phenotypic variability remains poorly understood. We employed cellular and mouse models to explore the allele-specific mechanisms associated with two novel mutations, a frameshift mutation and a missense mutation, in compound heterozygous that share the same splice-site pathogenic allele. In vitro, wild-type (WT) and mutant (c.574delC, c.1211C>A) SLC26A4 constructs were expressed in HeLa cells to assess pendrin localization. Both mutations reduced membrane enrichment and increased intracellular retention. In vivo, compound heterozygous knock-in mouse models (Slc26a4^{c.574delC/c.919-2A>G} and Slc26a4^{c.1211C>A/c.919-2A>G}) were generated using CRISPR/Cas9. The auditory function and cochlear pathology were investigated. Both compound mutants exhibited elevated ABR thresholds, with more severe hearing loss in Slc26a4^{c.574delC/c.919-2A>G} mice. Correspondingly, these mice showed marked hair cell disruption, stereociliary loss, and cochlear structural abnormalities, whereas the Slc26a4^{c.1211C>A/c.919-2A>G} mice displayed milder changes. Transcriptomic profiling examined by bulk RNA-sequencing revealed broader differential expression in Slc26a4^{c.574delC/c.919-2A>G} mice, enriched in structural and developmental pathways, while the missense model showed predominantly immune-related signatures. Our findings demonstrate that allele-specific functional divergence in compound heterozygous SLC26A4 mutations leads to distinct auditory dysfunction, cochlear pathology, and transcriptional programs. These findings provide mechanistic insight into the phenotypic heterogeneity of hearing loss and may indicate future allele-specific interventions or therapeutic strategies.

Hepatocellular carcinoma (HCC) exhibits marked sexual dimorphism, with females demonstrating superior survival, yet the underlying molecular mechanisms remain unclear. We integrated bulk transcriptomics (GSE39791, TCGA-LIHC, GSE14520) and single-cell RNA sequencing (five datasets, n = 58 patients, 238,982 cells) with machine learning (LASSO, SVM, random forest) to identify female-protective genes driving HCC disparities. Activating transcription factor 5 (ATF5) emerged as a female-protective gene with higher expression in females versus males across cohorts. Single-cell analyses revealed ATF5 defines a female-enriched, low-grade malignant subcluster with elevated apoptotic programs and reduced proliferative signaling, and pseudotime analysis showed coordinated ATF5-GPER1 downregulation during malignant progression (Spearman ρ = -0.52 and -0.48; both p < 0.001). In the immune compartment, ATF5 marked a female-enriched IFN-γ⁺ macrophage state with enhanced immunostimulatory programs and preferential CXCL9/10-CXCR3-mediated communication with CD8/NK cells. Mechanistically, ATF5 transcriptionally activates G protein-coupled estrogen receptor 1 (GPER1), forming an estrogen-responsive regulatory module that functionally suppresses proliferation, induces apoptosis (HepG2: 26.45% vs. 11.88%, p < 0.0001), and inhibits migration in a GPER1-dependent manner as demonstrated by rescue experiments. Tissue microarray validation (n = 167) confirmed high ATF5 expression predicts improved recurrence-free survival specifically in female patients (HR = 0.34, p = 0.040) but not males (p = 0.080). The ATF5-GPER1 axis represents a female-protective circuit operating through tumor-intrinsic suppression and immune remodeling, offering mechanistic insight into HCC sexual dimorphism and identifying ATF5 as a sex-specific prognostic biomarker with potential therapeutic implications.

Pancreatic cancer, and especially pancreatic ductal adenocarcinoma (PDAC), is extremely difficult to treat due to early asymptomatic stage, molecular heterogeneity, and resistance to conventional treatments, with a 5-year survival rate of less than 10%. Antibody-drug conjugates (ADCs), as an emerging precision therapy, show the potential to treat PDAC through the synergy of antibody targeting and cytotoxic drugs. Multiple targets (such as uPAR, Mesothelin, CLDN18.2, and TROP2) are highly expressed in PDAC, which has become the key direction of ADC development. However, the matrix barrier restricts drug delivery, heterogeneous expression leads to efficacy differentiation, and drug resistance mechanisms further limit the role of ADCs. To overcome these challenges, researchers are exploring high-stability single domain antibodies, more potent payloads and linkers, bystander effect mechanisms, and combined treatment strategies with immune, autophagy, DNA damage repair, and other pathways. Bispecific ADC, conditionally activated ADC, and penetration enhancement design have also been used to improve efficacy. On the whole, ADCs offer hope for the treatment of PDAC. Future research and development should focus on improving delivery efficiency, alleviating drug resistance, and individualized design.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited treatment options. Transient receptor potential ankyrin 1 (TRPA1) has been implicated in inflammation and pain, but its role in UC remains a subject of debate. The current study investigated the effects of TRPA1 inhibition in both acute and subacute murine models of dextran sulfate sodium (DSS)-induced colitis. Genetic knockout of Trpa1 or pharmacological inhibition with A967079 significantly ameliorated inflammation in the acute model, reducing the disease activity index (DAI), colon shortening, histopathological damage, and TNF-α secretion from macrophages. In contrast, TRPA1 suppression exacerbated subacute colitis and worsened weight loss, DAI, colon shortening, and histopathology. Mechanistically, Trpa1 deletion promoted CD4+ T cell polarization toward the Th1 subtype in subacute colitis, increasing IFN-γ levels. These findings reveal a dual role for TRPA1 in colonic inflammation: it mediates pro-inflammatory effects primarily via innate immune cells in the acute phase but has anti-inflammatory effects by modulating adaptive immunity in the subacute phase. These findings provide new insights into the context-dependent roles of TRPA1 and suggest that TRPA1 may represent a context-specific and stage-dependent therapeutic target in UC.

Closely associated with metabolic disorders, non-alcoholic fatty liver disease (NAFLD) substantially increases the risk of hepatocellular carcinoma. This study aimed to apply machine learning (ML) algorithms to a community-based cohort in southern Taiwan to identify key risk factors for NAFLD and to develop predictive models with clinical applicability. Data were derived from community health examinations, and eighteen clinical and demographic features were analyzed. Five ML algorithms were evaluated: logistic regression (LR), random forest (RF), K-nearest neighbors (KNN), adaptive boosting (AdaBoost), and extreme gradient boosting (XGBoost). Model performance was assessed using accuracy, precision, recall, F1 score, and area under the receiver operating characteristic curve (AUROC). A total of 7,510 participants were included (38.8% male; mean age 50.9 ± 15.0 years). The dataset was randomly divided into training (80%) and testing (20%) subsets, with no significant differences observed between groups in most independent variables. The Synthetic Minority Over-sampling Technique (SMOTE) was employed to balance NAFLD and non-NAFLD groups in the training dataset. Among all models, XGBoost achieved the highest performance, with an accuracy of 83.48%, precision of 84.31%, recall of 81.21%, F1 score of 82.72%, and AUROC of 92.85%. Feature importance analysis identified low-density lipoprotein cholesterol (LDL-C), body mass index (BMI), waist circumference, fasting plasma glucose (FPG), and triglycerides (TG) as the most influential predictors of NAFLD. ML algorithms, particularly XGBoost, demonstrated high accuracy in predicting NAFLD and effectively identified key clinical predictors. These findings may enhance early diagnosis and facilitate the development of targeted intervention strategies in the management of NAFLD.

This study investigates the prognostic significance of alpha-fetoprotein (AFP) in hepatitis B virus-related intrahepatic cholangiocarcinoma (HBV-ICC), given that AFP - though commonly used for hepatocellular carcinoma - is sometimes elevated in HBV-ICC, yet its clinical relevance remains unclear. The research retrospectively analyzed 839 HBV-ICC patients who underwent curative hepatectomy, categorizing them into AFP-positive (≥ 20 ng/mL) and AFP-negative groups. Using propensity score matching and inverse probability of treatment weighting to reduce bias, the study compared overall survival (OS) and time to recurrence (TTR). Results showed that AFP-positive patients had poorer liver function and more aggressive tumor characteristics, including higher rates of cirrhosis, microvascular invasion, and satellite nodules. Across both unadjusted and adjusted cohorts, elevated AFP was significantly associated with worse OS and earlier recurrence. Multivariate Cox analysis identified AFP as an independent predictor of poor prognosis. While CA19-9 alone demonstrated limited predictive value, its combination with AFP improved prognostic accuracy. The study concludes that elevated serum AFP independently predicts adverse survival and recurrence outcomes in HBV-ICC patients after curative resection, and combining AFP with CA19-9 enhances prognostic stratification, supporting AFP as a practical biomarker for postoperative risk assessment.

Inflammatory bowel disease (IBD) and physiological gut aging present with overlapping clinical features, including impaired barrier functioning, decreased nutrient absorption, and intestinal frailty. Emerging evidence indicates that even young IBD patients can exhibit gut phenotypes akin to those seen with aging. However, the two processes differ substantially in their underlying mechanisms. Gut aging is characterized by low-grade, chronic inflammation and gradual cellular senescence, whereas IBD involves persistent immune activation, cyclical tissue damage, and accelerated degenerative changes. This review systematically contrasts physiological gut aging and IBD-associated accelerated gut aging across several dimensions: cellular senescence and programmed cell death, immune cell remodeling, alterations in gut microbiota, changes in mesenteric adipose tissue, and the evolving role of the appendix. By integrating current advances in basic and translational research, this article highlights both the shared and distinct pathways driving gut dysfunction in aging and IBD, and underscores the importance of early recognition and targeted intervention for premature gut aging in clinical practice.

Mitochondria are organelles that play a crucial role in various physiological processes. They are particularly important during embryonic development, as their proper function is required for essential processes such as fertilization, implantation, and embryonic growth. In addition to their well-known role in adenosine triphosphate (ATP) synthesis and energy production, mitochondria serve multiple other functions during embryonic development. These include the synthesis of important metabolites, involvement in cell signaling pathways, regulation of reactive oxygen species, and facilitation of interactions between organelles. The mitochondrial genome, known as mitochondrial DNA (mtDNA), also plays a unique role in embryonic development. Dysfunction in mitochondria can lead to failures in fertilization, suboptimal embryo development, post-implantation failures, and mitochondrial-related diseases in adults. Advances in sequencing technology and experimental techniques have greatly improved our understanding of mitochondrial function. This paper reviews the roles of mitochondrial functions in embryonic development and the influence of mitochondrial technologies and it highlights the potential impact of understanding mitochondria's unique genetic and functional characteristics on embryonic development and offspring health.

Optimal post-remission therapy is crucial for long-term survival in patients with acute myeloid leukemia (AML). Multidisciplinary team (MDT) conferences address this challenge by providing comprehensive, patient-centered consultations that support individualized treatment decision-making. We evaluated the effectiveness of MDT conferences in guiding post-remission treatment decisions in adults with de novo AML. We enrolled 653 adult patients with de novo AML who were treated at our center between January 2017 and December 2022. Of the 591 eligible patients (90.5%), 501 (84.8%) attended a scheduled MDT evaluation. Allogeneic hematopoietic cell transplantation (allo-HCT) was recommended for 315 patients (62.9%), of whom 251 (79.7%) subsequently underwent transplantation. Survival analyses showed that MDT attendees had superior 3-year overall survival (68.9% vs. 53.5%, p < 0.0001) and a lower 3-year cumulative incidence of relapse (30.7% vs. 44.9%; p < 0.0001) compared with patients who did not attend MDT conferences. Patients most likely to benefit from allo-HCT following MDT recommendations included those with intermediate- or adverse-risk disease according to the European LeukemiaNet 2017 classification, and those with favorable-risk disease who showed a suboptimal response to induction therapy. The main barriers to allo-HCT were persistent or relapsed disease and patient preference. Overall, MDT conferences effectively identified patients who were most likely to benefit from allo-HCT and were associated with higher transplantation rates within a modern healthcare system.