Epithelial-mesenchymal transition is a crucial driver of cancer metastasis, enabling cancer cells to acquire invasive and migratory characteristics. This review synthesizes the molecular mechanisms underlying EMT, focusing on the transcription factors Snail, ZEB, and Twist, as well as the signaling pathways TGF-β/Smad and PI3K/Akt that regulate phenotypic plasticity. Components of the tumor microenvironment, including cytokines, hypoxia, and cancer-associated fibroblasts, synergistically activate EMT through dynamic interactions with oncogenic signaling pathways. The heterogeneity of EMT across different cancer types, such as hormone-mediated regulation in breast cancer and the involvement of non-coding RNAs in gastric malignancies, highlights its context-dependent role. Emerging therapies targeting EMT include small-molecule inhibitors, natural compounds, and herbal formulations, which aim to reverse EMT markers such as E-cadherin loss and vimentin upregulation, thereby sensitizing cancers to chemotherapy. Combinatorial approaches that integrate EMT suppression with conventional treatments show promise in overcoming drug resistance. However, challenges remain in clinical translation due to the plasticity of EMT and the adaptability of cancers. Future efforts should prioritize biomarker-driven strategies, and multi-omics approaches to refine the therapeutic targeting of EMT in metastatic cancers.
Background: Drug-induced chronic liver disease (DICLD) is concerned due to its threat to health, but there are few data about its global burden. We evaluated the trends in the burden of DICLD in 204 countries in thirty years via the Global Burden of Disease (GBD) database.
Methods: Death rates and disability-adjusted life year (DALY) rates of DICLD from 1990 to 2019 were the main outcomes. The global DICLD burden and health development status were assessed by age, sex, year, location, and sociodemographic index (SDI) quintiles. Trends were estimated via a joinpoint regression model (JRM).
Results: The global death rates of DICLD declined from 2.59 per 100,000 population in 1990-2.50 per 100,000 population in 2019 (-3.60%), and DALY rates declined from 89.59 per 100,000 population in 1990-82.17 per 100,000 population in 2019 (-8.28%). In 2019, the most severe deaths and DALY losses caused by DICLD were mainly concentrated in Europe, Asia and Africa, with a wide distribution in Europe and the most significant in Eastern Europe. Males had higher death rates and DALY rates than those of females, although they were declining. Old patients, especially those aged > 75 years, had a greater risk of DICLD. The death rates and DALY rates were the highest in low-middle-SDI countries.
Conclusions: This study revealed the global burden of DICLD on death rates and DALY rates, which were slightly decreased during the study period. More efforts are needed to better prevent and manage DICLD.
Background: Plasmacytoma variant translocation 1 (PVT1) is recognized as an oncogenic long non-coding RNA (lncRNA) in multiple cancer types including breast cancer (BC). Estrogen receptor alpha-positive (ERα+) BC is the major BC subtype, accounting for about 70% of cases. However, the role of PVT1 in this subtype and the underlying mechanisms are not yet fully elucidated.
Objective: To investigate the clinical significance and biological function of PVT1 in ERα+ BC.
Methods: The expression level and prognosis significance of PVT1 in ERα+ BC was explored through in silico analysis based on public databases. The biological function of PVT1 in ERα+ BC was examined in MCF7, a typical ERα+ BC cell line. MTS, plate clone formation and EdU assay were used to detect the effect of PVT1 knockdown on BC cell proliferation. The impact of PVT1 knockdown on estrogen signaling was assessed by measuring the expression of ERα and its downstream molecules through quantitative real-time PCR (qRT-PCR) and/or western blot. The regulatory effect of PVT1 on ERα was further investigated using protein stability experiments. To confirm the role of ERα in PVT1-regulated cell proliferation, rescue assay was conducted by targeting its downstream molecule BTG2.
Results: PVT1 expression is elevated in BC tissues compared to adjacent non-cancerous tissues, particularly in the ERα+ subtype. PVT1 knockdown substantially inhibited the proliferation of MCF7 cells as well as the estrogen signaling, which was evidenced by the marked downregulation of ERα and its downstream molecules including TFF1 and GREB1. Mechanistically, PVT1 knockdown was proved to significantly accelerate the degradation of ERα protein. BTG2 is a downstream molecule negatively regulated by ERα, which was upregulated upon PVT1 knockdown. In the rescue assay, interference of BTG2 could largely attenuated the inhibitory effect of PVT1 knockdown on cell proliferation.
Conclusion: PVT1 knockdown could inhibit cell proliferation partly through disrupting the ERα-BTG2 axis in ERα+ breast cancer.
Background: Guizhi Gancao Decoction (GGD), a classic formula in Traditional Chinese Medicine (TCM), is composed of Ramulus Cinnamomi (RC) and Radix Glycyrrhizae (RG). It is traditionally used to restore heart Yang and promote Qi transformation. However, its anti-cold effects, underlying mechanisms, and primary active components remain to be fully elucidated.
Objective: To investigate the anti-cold activity of GGD, identify its primary active components, and further explore its underlying mechanisms.
Methods: Mice were randomized into six groups (n = 10): control (no cold exposure), model (cold exposure), Miglitol (50 mg/kg, cold exposure), and three GGD groups (1, 2, 4 g/kg, cold exposure). After 21 days of treatment, body temperature and athletic performance were assessed. The main components of GGD were identified using HPLC-Q-TOF-MS, and network pharmacology was employed to analyze key compounds, targets, and biological processes. The pivotal signaling pathway was experimentally validated.
Results: GGD significantly alleviated hypothermia induced by cold exposure, while reducing total cholesterol, lipid droplets, mitochondrial membrane potential, and Adenosine
Triphosphate (ATP) production in brown adipose tissue (BAT). Additionally, GGD significantly upregulated the expression of Uncoupling protein 1 (UCP1) and its upstream regulator, Peroxisome proliferatoractivated receptor γ (PPARγ).
Conclusions: Administration of GGD maintains core body temperature during cold exposure by activating BAT via the PPARγ signaling pathway. The key compounds licochalcone D, hispaglabridin A, and cinnamic acid target PPARγ, UCP1, and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) respectively, regulating fatty acid oxidation and lipid metabolism. These compounds contribute to enhanced thermogenesis via PPARγ pathway. The prescription has the potential to be developed as a medicine for increasing thermogenesis in cold conditions.
Precision medicine refers to tailoring therapeutic interventions to an individual’s genetic, molecular and phenotypic characteristics, while multi-omics integrates genomics, proteomics and metabolomics data to provide a systems-level view of disease. Together with artificial intelligence (AI) driven predictive modeling, these approaches enable early identification of cardiotoxic risk and optimization of drug therapy in cardiovascular diseases. The present review explores the possibility of precision medicine to overcome cardiotoxicity associated with conventional cardiovascular disease (CVD) treatments. It highlights the integration of biomarker-driven therapies, pharmacogenomics, and multi-omics technologies to improve therapeutic efficacy and minimize the risk of adverse drug reactions. Additionally, the review assesses the emerging contributions of artificial intelligence (AI) and network medicine in improving cardiovascular diagnostics and developing personalized treatment regimens. The discovery of genomics, proteomics, metabolomics into cardiovascular research has significantly increased our understanding in disease etiology and variability in response of drug. Furthermore, AI-driven predictive models and machine learning algorithms play key role in minimizing clinical risk and support precision-guided decision, ultimately enhance patient outcomes. The advancement in omics technology, AI and customized therapy is expected to revolutionize cardiovascular care, despite current challenges in clinical implementation. The integration of cutting-edge approaches into standard clinical practice would maximize treatment effectiveness and guarantee patient safety.
Cells secrete a diverse array of extracellular vesicles (EVs) to mediate intercellular communication, profoundly influencing both physiological and pathological processes through the transfer of proteins, lipids, and genetic material. Among these, blebbisomes have recently emerged as a novel, large (up to 20 µm), organelle-rich EV subtype, distinguished by their dynamic membrane blebbing and active release from cells. Blebbisomes harbor a spectrum of intact organelles, including functional mitochondria and multivesicular endosomes, yet notably lack a nucleus. Their enrichment with immune checkpoint proteins in cancer underscores a potential role in immune regulation and tumor progression, positioning them at the forefront of research into disease mechanisms. The unique structural and functional attributes of blebbisomes highlight their potential significance as a crucial way of communication and promising targets for therapeutic innovation. This review synthesizes current advances in isolation, characterization, and functional understanding of blebbisomes, illuminating their emerging roles in health and disease.
The FAERS database is a vital tool for identifying adverse drug reactions (ADRs). However, data mining in FAERS faces significant challenges, including data quality issues (e.g., integrity, consistency, and completeness) and limitations in traditional model selection. These issues can introduce biases and affect the reliability of safety signal detection. This review critically analyzes the current state and limitations of FAERS data mining, particularly by briefly comparing it with other mainstream global databases to contextualize its unique challenges. It then proposes optimization strategies, focusing on improved data preprocessing, algorithm refinement, and the integration of emerging technologies. We emphasize the potential of Artificial Intelligence (AI) and multi-source data fusion to enhance detection sensitivity, accelerate the risk signal identification cycle, and address challenges in data-limited scenarios, such as rare diseases. We recommend promoting database standardization, strengthening validation, and formulating policy changes to fully realize FAERS's potential for precision pharmacovigilance.
Acid-related diseases (ARDs) are characterized by high incidence rates and significant disease burden. Excessive gastric acid secretion or heightened gastric acid sensitivity is the common pathogenesis of these conditions, leading to the widespread application of the principle of "treating different diseases with the same therapy" in medication management. With increasing concerns about the risks of inappropriate use of acid-suppressing drugs like proton pump inhibitors (PPIs), there is an urgent need to deepen the systematic understanding of medication therapy for acid-related diseases and to promote rational drug use. This consensus was developed by a multidisciplinary panel of experts in clinical medicine, pharmacy, and methodology. Based on evidence-based medicine, it provides a systematic elaboration on the classification of ARDs, therapeutic drugs, diagnostic methods, and pharmaceutical care services. Additionally, it offers consensus-based recommendations and management strategies for key clinical issues encountered in practice. The release of this consensus is of great significance for establishing a medication therapy management system and promoting rational drug use for acid-related diseases.
Objective: To systematically summarize the clinical data from phase II-IV studies of nemonoxacin malate and comprehensively evaluate the clinical efficacy of nemonoxacin in treating pneumonia caused by atypical pathogens, so as to inform empirical antimicrobial selection in clinical practice.
Methods: A retrospective analysis was performed on the results of four phase II/III clinical studies of nemonoxacin malate in patients with community-acquired pneumonia (CAP) and on the composition and clinical outcomes of atypical pathogen-infected patients in one phase IV clinical study; subgroup efficacy analyses were conducted by age and by presence or absence of co-pathogen infection.
Results: This study included four phase II/III controlled trials and one phase IV single-arm trial, with a primary analysis population of 1769 CAP patients, of whom 994 were male (56.2%) and 775 were female (43.8%), with a mean age of 47.83 ± 16.39 years. In the phase II/III studies, 370 patients (27.8%) were positive for atypical pathogens, including Mycoplasma pneumoniae (MP) in 265 cases (19.9%), Chlamydia pneumoniae (CP) in 68 cases (5.1%), and Legionella pneumophila (LP) in 85 cases (6.4%). In the phase IV study, 172 patients (39.7%) were positive for atypical pathogens, including PM in 141 cases (32.6%), CP in 14 cases (3.2%), and LP in 50 cases (11.5%).Efficacy analysis showed that nemonoxacin 500 mg oral and injectable formulations had clinical success rates against atypical pathogens of 98.0% vs levofloxacin 95.5% (oral) and 97.7% vs levofloxacin 95.8% (injectable), respectively; against MP the rates were 99.0% vs 94.1% (oral) and 97.6% vs 100.0% (injectable), respectively, suggesting that the clinical efficacy of the two formulations of nemonoxacin is slightly superior to or comparable with levofloxacin. Additionally, subgroup analyses stratified by age and by presence of co-pathogen infection showed that nemonoxacin demonstrated good clinical efficacy in patients aged both < 60 years and ≥ 60 years, regardless of whether the infection was solely due to atypical pathogens or accompanied by other pathogens.
Conclusion: Nemonoxacin demonstrated good clinical efficacy in CAP patients with atypical pathogen infections, with effects comparable to or superior to levofloxacin, and may be considered as one of the options for empirical CAP treatment or as a therapeutic choice after confirmation of atypical pathogen infection.
Background: Antimicrobial resistance (AMR) threatens global health. Conventional fluoroquinolones have experienced accelerated resistance due to target-enzyme mutations and are further constrained by safety concerns. Nemonoxacin, as the first non-fluorinated quinolone, overcomes the aforementioned drawbacks by removing the fluorine atom at C-6 and introducing a methoxy substitution at C-8, but the trends in its antibacterial activity and the evolution of its antimicrobial spectrum remain unclear.
Objective: To assess the long-term evolution of the antibacterial activity of the novel non-fluorinated quinolone nemonoxacin against clinical isolates, evaluate its resistance risk, and compare it with conventional quinolones.
Methods: Clinical Gram-positive and Gram-negative isolates were collected from a multicenter network of 22 hospitals nationwide between 2015 and 2024. Minimum inhibitory concentrations (MICs) of nemonoxacin and comparator drugs were determined by agar dilution according to the Clinical and Laboratory Standards Institute (CLSI) standards; MIC trends were analyzed using Spearman's rank correlation coefficient and the Cochran-Armitage trend chi-square test.
Results: Nemonoxacin exhibited markedly superior antibacterial activity against Gram-positive bacteria compared with conventional quinolones. During the 10-year surveillance period, the isolation rate of methicillin-resistant Staphylococcus aureus (MRSA) was 34.95% and that of methicillin-resistant Staphylococcus epidermidis (MRSE) was 82.08%. The susceptibility rate of MRSA to nemonoxacin was 78.5%, and susceptibility rates among other staphylococci were all ≥ 80%, which is 19.4%-27.7% higher than that of conventional quinolones; for Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, and the viridans group streptococci, the MIC50 and MIC90 values were 1/2-1/64 those of fluoroquinolones, with a susceptibility rate of 99.4%. Among Gram-negative bacteria, Escherichia coli (extended-spectrum β-lactamase [ESBL]-positive rate 53.3%) and Klebsiella pneumoniae (ESBL-positive rate 23.5%) showed susceptibility rates to nemonoxacin of 41.0% and 60.9%, respectively, outperforming ciprofloxacin and levofloxacin; carbapenem-susceptible, ESBL-negative K. pneumoniae had a susceptibility rate up to 90.2%. For Haemophilus influenzae, nemonoxacin MICs ranged from 0.004 to 8 mg/L, which are 1/2-1/4 those of other quinolones; for Moraxella catarrhalis, the MICs were similar to those of fluoroquinolones. The resistance of Staphylococcus aureus and Escherichia coli to nemonoxacin showed a declining trend compared with the start year, manifesting as a “reverse MIC drift,” and the decrease in S. aureus resistance was not significantly correlated with the decline in MRSA isolation rate. Among Gram-positive bacteria, isolates from intensive care unit (ICU) patients and elderly patients, as well as S. aureus recovered from sputum and urine specimens, exhibited higher rates of resistance to nemonoxacin than isolates from other sources; among Gram-negative bacteria, ICU-isolated Klebsiella pneumoniae, Haemophilus influenzae isolated from adult patients, and Escherichia coli and K. pneumoniae isolated from urine specimens showed higher nemonoxacin resistance rates than isolates from other sources.
Conclusion: By virtue of its non-fluorinated structure and dual-target mechanism, nemonoxacin effectively curtailed the development of resistance over the 10-year period, demonstrating a sustained advantage particularly in infections caused by S. aureus, Streptococcus pneumoniae, and H. influenzae. The maintained or improved trend in its antibacterial activity suggests that, through the synergy of structural innovation and precision use, reversal of resistance evolution may be achievable, providing a new direction for optimizing anti-infective therapy.