Current Issues in Molecular Biology最新文献

Steatosis extends beyond the liver to the pancreas, heart, and skeletal muscle, yet prevailing definitions remain narrowly organ-focused. This narrative review introduces the Metabolic Steatotic Axis (MSA) as a framework that captures the dynamic, bidirectional interactions among these organs, driving systemic metabolic dysfunction. We synthesize evidence linking lipotoxicity, inflammatory signaling, and endocrine cross-talk into a self-amplifying network accelerating insulin resistance, β-cell failure, and cardiometabolic risk. The MSA concept provides a rationale for axis-based staging systems and composite biomarker panels to quantify cumulative disease burden better and refine risk stratification. We highlight phenotypic heterogeneity within MSA stages, the possible hierarchy of organ vulnerability, and the implications for prognosis and therapy. Viewing pharmacological and lifestyle interventions through the MSA lens reframes them as systemic modulators rather than organ-specific treatments, underscoring the need for multi-organ endpoints in clinical trials. Finally, we outline priorities for longitudinal imaging, multi-omics integration, and global harmonization to translate the MSA from a conceptual construct to a clinically actionable paradigm. By unifying fragmented observations into a systemic model, the MSA has the potential to reshape disease classification, therapeutic strategies, and precision medicine in metabolic disorders.

Genomic instability not only drives tumor initiation and progression but also cooperates with apoptosis resistance to promote therapeutic evasion in hepatocellular carcinoma (HCC). Activation of MDM2, a negative regulator of p53, together with XIAP overexpression, represents a critical axis underlying this resistance. Simultaneous targeting of MDM2 and XIAP by MX69, a small molecule inhibitor, may therefore offer a potent interventional strategy to suppress cell proliferation and enhance pro-apoptotic signaling in HCC in vitro models. To evaluate the effects of MX69, cell viability was assessed via CVDK-8, colony formation, and real-time cell analysis. Oxidative stress levels and DNA damage were examined using fluorescence imaging and comet assays, respectively, while mitochondrial membrane potential was monitored through JC-1 staining. Furthermore, flow cytometry was employed to quantify apoptotic cell death and cell cycle distribution, while Western blot analysis was used to characterize the expression of apoptosis-related proteins. In vitro cytotoxicity assays revealed that MX69 reduced the viability of HUH7 and Hep3B cells in a dose-dependent manner, suppressed colony formation, and exerted anti-proliferative effects in real-time proliferation assays. Cell viability and IC50 values were evaluated using CVDK-8 and RTCA assays. Furthermore, MX69 induced oxidative stress and mitochondrial dysfunction, as evidenced by elevated ROS levels and loss of mitochondrial membrane potential. This was accompanied by significant DNA damage, detected by comet assay and γ-H2AX immunofluorescence, and G0-G1 cell cycle arrest. Moreover, MX69 triggered apoptotic cell death, demonstrating potent anticancer activity. Collectively, our findings identify MDM2/XIAP dual inhibition by MX69 as a promising therapeutic approach in HCC, with potential to overcome apoptosis resistance linked to genomic instability.

Meconopsis quintuplinervia is traditionally used in Tibetan medicine for diseases of the lung and liver. This study investigated the antioxidant and anti-inflammatory activities of its extract (MQ extract), analyzed its chemical composition, and explored the potential therapeutic mechanisms against chronic obstructive pulmonary disease (COPD) and non-alcoholic fatty liver disease (NAFLD) using network pharmacology. MQ extract demonstrated effective scavenging of DPPH and ABTS radicals, with activity comparable to ascorbic acid and Trolox. In cellular assays, the extract dose-dependently reduced ROS levels in H₂O₂-induced B16-F10 and RAW264.7 cells and significantly inhibited NO production in LPS-stimulated RAW264.7 macrophages. Quantitative analysis showed total phenolic content of 90.54 ± 0.91 mg/g and total flavonoid content of 44.48 ± 0.43 mg/g. LC-MS/MS analysis identified taxifolin as the predominant constituent at approximately 2.39%. Network pharmacology and molecular docking studies revealed that flavonoids including catechin, isorhamnetin, kaempferol, luteolin, naringenin, nobiletin, quercetin, and taxifolin interacted with therapeutic targets for COPD and NAFLD. These compounds likely exerted effects by inhibiting NF-κB signaling, downregulating pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and enhancing antioxidant enzyme activities (SOD), while also reducing hepatic lipid accumulation through SREBP-1 suppression. Our findings elucidated why Tibetan medicine traditionally uses M. quintuplinervia to treat pulmonary and hepatic disorders.

Sepsis is frequently accompanied by myocardial dysfunction, which significantly worsens clinical outcomes. Lipopolysaccharide (LPS), a key component of Gram-negative bacteria, induces excessive oxidative stress and apoptosis in cardiomyocytes, contributing to sepsis-associated cardiac injury. Plasma-derived extracellular vesicles (EVs) have emerged as important mediators of intercellular communication and cardiovascular protection; however, their role in LPS-induced cardiomyocyte injury remains unclear. In this study, human AC16 cardiomyocytes were exposed to LPS in the presence or absence of plasma-derived EVs. Intracellular reactive oxygen species (ROS) production and apoptosis were assessed by flow cytometry, while apoptosis-related proteins and NF-κB signaling components were analyzed by Western blotting. The involvement of NF-κB signaling was further examined using pharmacological rescue experiments. Our results demonstrate that EV treatment markedly attenuated LPS-induced ROS accumulation and cardiomyocyte apoptosis. These protective effects were associated with reduced phosphorylation of NF-κB p65 and IκBα, as well as inhibition of p65 nuclear translocation. Notably, activation of NF-κB signaling abolished the anti-apoptotic and antioxidative effects of EVs under LPS challenge. Collectively, these findings suggest that plasma-derived EVs mitigate LPS-induced oxidative stress and apoptosis in human cardiomyocytes, potentially through modulation of NF-κB signaling. This study provides molecular insights into the cardioprotective actions of EVs and supports their potential as therapeutic candidates for sepsis-associated cardiovascular dysfunction.

Due to the limited data on chemical coding of sympathetic chain ganglia neurons during the prenatal period, this study, for the first time, aimed to characterise noradrenergic and cholinergic neurotransmitter expression in lumbar sympathetic chain ganglia (L SChG) of 5-, 7-, and 10-week-old porcine foetuses as a model increasingly recognised in biomedical research. Double immunohistochemical staining was performed using antibodies against PGP 9.5 (marker of neuronal structures), β-hydroxylase tyrosine (DβH), and vesicular acetylcholine transporter (VAChT). The current findings demonstrated that, in 5-week-old foetuses, approximately 79.83 ± 4.37% of nerve cell bodies were DβH-positive, 25.90 ± 5.60% contained VAChT, and some neurons were DβH/VAChT-positive (12.45 ± 4.36%). In 7-week-old foetuses, the proportion of DβH-positive neurons increased to 82.0 ± 9.7%, while VAChT-positive neurons decreased to 6.5 ± 1.0%, and 9.1 ± 0.7% DβH-positive L SChG perikarya contained VAChT. In 10-week-old foetuses, DβH-positive neurons accounted for 88.5 ± 2.1%, VAChT-positive for 1.98 ± 0.64%, and DβH/VAChT-positive perikarya decreased to 5.4 ± 0.4%. These findings provide new insight into the differentiation of the autonomic nervous system and the timing of neurotransmitter phenotype specification. Understanding the ontogeny of noradrenergic and cholinergic neurons may contribute to a better understanding of developmental disorders affecting the autonomic nervous system and may have implications for regenerative medicine, neurodevelopmental diagnostics, and therapeutic strategies targeting sympathetic dysfunction.

Castanea henryi is an important economic tree species in China. Its nutrient-rich nuts play a key role in raising farmers' income in mountainous areas, promoting forestry industry development, and maintaining ecological balance, thereby providing significant economic and ecological value. To systematically elucidate the genetic characteristics of major C. henryi cultivars in China, this study conducted phenotypic trait measurements on 42 cultivars collected from Taining and Jian'ou in Fujian Province. Combined with whole-genome resequencing technology and using the C. henryi genome as a reference, systematic analyses were carried out. The results indicated that the Jian'ou group (HJO) generally exhibited superior performance in key fruit phenotypic traits compared to the Taining group (HTNC), with greater phenotypic diversity observed within the HJO group. Clustering analysis of phenotypic traits further revealed a cross-geographic convergent clustering pattern among the 42 C. henryi cultivars. Further analysis revealed that the overall genetic diversity of the 42 C. henryi cultivars was relatively low (observed heterozygosity: HJO = 0.0275, HTNC = 0.0194). Notably, parameters such as heterozygosity, minor allele frequency, nucleotide polymorphism, and polymorphic information content were slightly higher in the Jian'ou group compared to the Taining group. Divergent selection signal analysis (Fst top 5%) identified 3129 genomic regions under divergent selection. Genes within these regions showed homology to 1205 Arabidopsis thaliana genes, reflecting adaptive divergence driven by differential historical selection pressures between the two groups. Population genetic structure analysis indicated that the two regional groups exhibit high genetic similarity and low differentiation. This study reveals low genetic diversity and high genetic background homogeneity among C. henryi cultivars, findings that could inform the design of future breeding strategies.

Pre-eclampsia is a Hypertensive Disorder of Pregnancy (HDP) characterized by hypertension and proteinuria, affecting 2-8% of pregnancies worldwide and constituting a major public health concern. Genes of the renin-angiotensin system have been investigated as potential causative factors, but inconclusive results have been obtained. The objective of this pilot study is to evaluate the possible contribution of alleles, genotypes or haplotypes of two single-nucleotide polymorphisms (SNPs) T174M (rs4762) and M235T (rs699) in AGT gene to pre-eclampsia in the Mexican population. We analyzed the association by performing PCR-RFLP with DNA extracted from whole blood samples of Mexican women with pre-eclampsia or normotensive pregnancy and the general population (GP). Our results showed a significant difference in the rate of heterozygosity for the T174M polymorphism between cases and controls. In addition, this polymorphism together with homozygosity for the M235T polymorphism may represent a possible genetic marker associated with pre-eclampsia. The T-C haplotype (174M-M235) was more common in patients with pre-eclampsia (non-significant difference p = 0.0503). The identification of genetic risk markers may support the early detection of pre-eclampsia and strengthen peripartum maternal health strategies within a global health framework aimed at reducing maternal mortality.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, primarily driven by chronic inflammation from viral hepatitis, metabolic dysfunction, alcohol-induced liver disease, and cirrhosis. Conventional therapies often fail in advanced stages, highlighting the need for mechanism-based, precision-guided interventions. Plant-derived secondary metabolites represent a promising class of bioactive compounds with structural diversity, multitarget activity, anti-inflammatory effects, and favorable toxicity profiles. This review follows a semi-systematic narrative that synthesizes preclinical and experimental evidence on the anti-inflammatory and anticancer properties of key phytochemicals, including epigallocatechin-3-gallate, galangin, resveratrol, quercetin, curcumin, berberine, genistein, and thymoquinone. These compounds consistently modulate critical inflammation-driven signaling pathways, PI3K/AKT/mTOR, NF-κB, JAK/STAT, Wnt/β-catenin, and MAPK, resulting in apoptosis induction, cell cycle arrest, inhibition of angiogenesis, and reduced invasion and metastasis in multiple HCC models. Despite strong preclinical evidence, clinical translation remains limited by variable bioavailability, incomplete safety data, and insufficient human studies. A staged development strategy is recommended: standardized formulations, Good Laboratory Practice-compliant pharmacokinetic/toxicology studies, validation in patient-derived models, and early-phase, biomarker-guided clinical trials with combination therapy arms. Addressing regulatory, manufacturing, and quality control considerations will be essential for advancing these compounds as adjuvant or complementary agents in precision HCC therapy.

Post-transcriptional regulation of gene expression is influenced by RNA-binding proteins (RBPs) and small non-coding RNAs that bind to conserved mRNA sequences to modulate mRNA processing. These regulatory molecules affect the structural conformation of mRNAs, creating formations like G-quadruplexes (G4s), which alter translation initiation and regulatory-factor site accessibility. Recent studies have highlighted Nuclear factor erythroid 2-related factor 2 (NRF2) as a key regulator of cellular redox homeostasis and cellular response to oxidative stress. An intriguing feature of NRF2 is the structural formation of its 5' untranslated region (UTR), which may promote or inhibit translation initiation depending on the cellular context. In this study with minigenes, we provide in vitro evidence of RNA G4s in the NRF2 mRNA's 5' UTR under basal (no stress) conditions. Achieved via electrophoretic mobility shift assay and fluorescence spectra in the presence of Pyridostatin. Understanding how structural motifs within NRF2 5' UTRs influence mRNA function provides insights into a common molecular mechanism underlying diseases where NRF2 is dysregulated, like cancers, cardiovascular disease, and neurodegeneration, and highlights potential therapeutic avenues through regulation of NRF2.

Over the past two decades, advances in the understanding of epigenetic mechanisms-driven by the rapid expansion of omics technologies-have catalyzed a major paradigm shift in biology: from the genetic determinism and linear causality of the Central Dogma toward the dynamic, networked complexity of systems biology and multilevel regulation. This reconceptualization extends to inheritance itself, highlighting the crucial role of the epigenome as a molecular interface between the genome and the exposome-the cumulative set of internal and external environmental influences experienced across the lifespan. Within this evolving framework, neurodevelopmental disorders exemplify the deep entanglement between genetic predisposition, environmental exposure, and epigenetic modulation. Their increasing global prevalence and frequent comorbidities underscore the need for an integrated etiological understanding that transcends reductionist models. This review tries to synthesize current evidence on the shared molecular and systemic mechanisms underlying neurodevelopmental spectrum disorders and examines how environmental and epigenetic factors jointly shape neurodevelopmental trajectories across generations. Finally, it discusses the broader implications of this paradigm shift for early diagnosis, prevention, and public health policies aimed at fostering healthy brain development in future generations.