p21 (encoded by the CDKN1A gene) is a critical cell cycle regulatory protein endowed with versatile biological functions. In various sex hormone-related cancers, p21 exhibits a paradoxical dual role, capable of both inhibiting tumorigenesis and promoting cancer progression, exerting dual, often opposing, effects on cellular fate that are dictated by the specific context. The clinical targeting of p21 remains elusive, largely due to its functionally pleiotropic and context-dependent nature within intricate regulatory networks. During the initial, hormone-dependent phase of cancers like breast and prostate cancer, p21 expression and activity are largely governed by the transcriptional programs of estrogen or androgen receptor signaling. This hormonal regulation contributes to the control of tumor cell proliferation and underpins the initial efficacy of endocrine therapies. In contrast, as these diseases advance to late stages or evolve into non-hormone-dependent subtypes—exemplified by castration-resistant prostate cancer (CRPC) and specific forms of triple-negative breast cancer (TNBC)—these conventional hormonal control mechanisms often become dysfunctional or are entirely bypassed. This fundamental transition creates a critical therapeutic void, highlighting the urgent need to identify and exploit alternative molecular pathways to effectively target p21’s function. Promising strategies may include the precise modulation of its upstream transcriptional regulators, downstream effector proteins, or the intersecting parallel signaling networks that critically influence its activity. This review provides a systematic synthesis of the intricate and interconnected mechanisms that underpin the dual effects of p21 in sex hormone-related tumors. These mechanisms are categorized into three core, interrelated functional domains. (1) cell cycle regulation: p21 executes its canonical tumor-suppressive role by binding to and inhibiting cyclin-dependent kinases (CDKs) and by directly interacting with proliferating cell nuclear antigen (PCNA), thereby inducing cell cycle arrest, predominantly at the G1/S checkpoint; (2) apoptosis modulation: p21 exerts a highly context-dependent influence on programmed cell death, functioning either as a pro-apoptotic agent under severe genotoxic stress or as a pro-survival factor by inhibiting apoptosis through interactions with proteins like Bcl-2; (3) hormonal and signaling crosstalk: p21 is an integral node within broader cellular networks, engaging in direct physical interactions with hormone receptors(e.g., AR, ER) and participating in complex feedback loops with key oncogenic pathways, including PI3K/AKT, MAPK/ERK, and p53. Critically, the role of p21 is not static but highly dynamic. It can undergo a functional switch from tumor-suppressive to tumor-promoting in response to therapeutic pressures, metabolic alterations, or evolving tumor microenvironment cues. These adaptive shifts are frequently implicated in the development of therapy resistance and disease recurrence, particularly in advanced, hormone-resistant cancers. By synthesizing these insights, this review aims to establish a coherent theoretical framework to guide the future development of novel therapeutic strategies that target the p21 pathway. It underscores the necessity of moving beyond a simplistic, binary view of p21 and emphasizes the forthcoming challenges, such as the discovery of reliable biomarkers to predict its functional state and the rational design of context-specific pharmacological modulators to selectively harness its therapeutic potential.

Background: and Purpose Vertebrobasilar fusiform aneurysms (VBFAs) carry substantial morbidity and mortality, but optimal management for unruptured VBFAs remains unclear. We compared the safety and efficacy of conservative management (CM), stent-assisted coiling (SAC), and flow diverters (FDs) in patients with unruptured VBFAs, focusing on long-term prognosis. Methods: This study included data from a nationwide Chinese cohort of patients with vertebrobasilar dissecting aneurysms. Inverse probability of treatment weighting (IPTW) balanced confounders across groups. The primary outcome was poor prognosis (modified Rankin Scale score >2). Secondary outcomes included aneurysm rupture, ischemic stroke, compression symptoms, and VBFA-related deaths. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were performed. Results: Among 1,115 patients with unruptured VBFAs, 838 (median age, 54 years; 655 men) were included. After IPTW, baseline characteristics were balanced. Median follow-up was 54 months. FD was associated with a lower risk of poor prognosis than CM (OR, 0.48 [95% CI, 0.30 to 0.77]; p=0.002), with no difference between CM and SAC. FD also reduced aneurysm rupture (OR, 0.20 [95% CI, 0.07 to 0.60]; p=0.004) and compression symptoms (OR, 0.30 [95% CI, 0.13 to 0.68]; p=0.004) versus CM. Time-to-event analyses further revealed significant differences in vertebral artery lesions and Type I–II VBFAs, whereas no significant differences were observed in basilar or vertebrobasilar junction lesions or in Type III–IV VBFAs. Conclusions Compared with CM, FD was associated with improved long-term outcomes in unruptured VBFAs, particularly in vertebral artery lesions and Type I–II VBFAs, although residual confounding cannot be excluded.

Background: Visceral white adipose tissue (vWAT) inflammation is a critical pathology of obesity-caused heart damage and is closely associated with adipocyte endoplasmic reticulum (ER) dysfunction. Serine (or cysteine) peptidase inhibitor, clade A, member 3C (Serpina3c) has been identified as an adipokine with anti-vWAT inflammatory effects. However, it remains unclear whether Serpina3c deficiency promotion of vWAT inflammation involves adipocyte ER dysfunction and whether it further contributes to heart damage in obesity. Methods: Wild type and Serpina3c knockout (Serpina3c–/–) mice were fed a high-fat diet (HFD) for 12 weeks. An adeno-associated virus (AAV) was injected locally into epididymal white adipose tissue (eWAT) of Serpina3c–/– mice to induce eWAT-adipocyte- specific overexpression of Serpina3c (AAV-Serpina3c) or knockdown of hypoxia-inducible factor 1α (AAV-shHIF1α). In vitro experiments were performed in 3T3-L1 adipocytes. Results: Serpina3c–/– mice exhibited more severe eWAT, serum and heart inflammation after HFD feeding. Consistently, these adverse phenotypes were mitigated in AAV-Serpina3c and AAV-shHIF1α mice. Mechanistically, ER oxidoreductase 1α (Ero1α) and protein disulfide isomerase (PDI) family members PDIA3 and PDIA4 were found to be target genes of HIF1α. In the obese mice, Serpina3c deficiency caused adipocyte more hypertrophy, and activated HIF1α-Ero1α/PDI mediated ER overoxidation and ER stress in eWAT. Subsequently, this led to increased adipocyte apoptosis and chemokine production and decreased adiponectin expression, which promoted macrophage infiltration and M1 polarization in eWAT, thus exacerbating eWAT inflammation and ultimately facilitating serum and distal heart inflammation. Conclusion These findings indicate that Serpina3c is a significant regulator of adipocyte ER redox homeostasis, thus highlighting Serpina3c as a potential therapeutic target for obesity-related eWAT inflammation and heart damage.

ObjectiveTo clarify whether METTL14 mediates the core role of acupuncture at Neiguan (PC6) in promoting myelination and improving behavior in young autistic rats through gene intervention technology. MethodsThe ASD model was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats. Male offspring were intracerebroventricularly injected with adenovirus-packaged METTL14 shRNA (sh-METTL14) or its control (sh-NC) on postnatal day 1, with a model group set as well. Subsequently, the juvenile rats were divided into model group, acupuncture group, acupuncture+sh-NC group, and acupuncture+sh-METTL14 group. The acupuncture group received acupuncture at Neiguan (PC6) from postnatal day 7, once daily for 21 consecutive days. Neurobehavioral changes were evaluated by behavioral tests; METTL14 knockdown efficiency and the expression of METTL14, METTL3, and PTEN were detected by quantitative real-time PCR (qRT-PCR) and Western blot (WB); PTEN m⁶A levels were measured by RNA immunoprecipitation-qPCR (RIP-qPCR); myelin ultrastructure, expression of myelin basic protein (MBP) and neurofascin 155 (NF155), and dendritic spine density were observed using transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, qRT-PCR, and primary neuron culture. ResultsBehaviorally, knockdown of METTL14 significantly counteracted the beneficial effects of acupuncture in improving self-grooming, open field exploration, three-chamber social interaction, and Morris water maze learning and memory (P<0.05, P<0.01). Compared with the acupuncture+sh-NC group, the acupuncture+sh-METTL14 group showed significantly decreased mRNA and protein expression of hippocampal METTL14 (P<0.01), and the upregulating effects of acupuncture on METTL3 and PTEN expression were reversed (P<0.01). Meanwhile, knockdown of METTL14 significantly inhibited the acupuncture-induced increase in PTEN m⁶A levels (P<0.01). Morphologically, knockdown of METTL14 attenuated the improvement of myelin structure by acupuncture, reversed the downregulation of MBP and upregulation of NF155 induced by acupuncture, and blocked the increase in dendritic spine density (P<0.05, P<0.01). ConclusionMETTL14 is a key molecule mediating the therapeutic effect of acupuncture at Neiguan. Acupuncture at Neiguan upregulates METTL14, thereby enhancing m⁶A methylation modification of PTEN mRNA to stabilize its expression, ultimately promoting myelin development and improving behavioral symptoms in ASD juvenile rats. This preliminarily reveals the modern biological connotation of “opening Xuanfu and dredging myelin”.

ObjectiveTo clarify whether METTL14 mediates the core role of acupuncture at Neiguan (PC6) in promoting myelination and improving behavior in young autistic rats through gene intervention technology. MethodsThe ASD model was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats. Male offspring were intracerebroventricularly injected with adenovirus-packaged METTL14 shRNA (sh-METTL14) or its control (sh-NC) on postnatal day 1, with a model group set as well. Subsequently, the juvenile rats were divided into model group, acupuncture group, acupuncture+sh-NC group, and acupuncture+sh-METTL14 group. The acupuncture group received acupuncture at Neiguan (PC6) from postnatal day 7, once daily for 21 consecutive days. Neurobehavioral changes were evaluated by behavioral tests; METTL14 knockdown efficiency and the expression of METTL14, METTL3, and PTEN were detected by quantitative real-time PCR (qRT-PCR) and Western blot (WB); PTEN m⁶A levels were measured by RNA immunoprecipitation-qPCR (RIP-qPCR); myelin ultrastructure, expression of myelin basic protein (MBP) and neurofascin 155 (NF155), and dendritic spine density were observed using transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, qRT-PCR, and primary neuron culture. ResultsBehaviorally, knockdown of METTL14 significantly counteracted the beneficial effects of acupuncture in improving self-grooming, open field exploration, three-chamber social interaction, and Morris water maze learning and memory (P<0.05, P<0.01). Compared with the acupuncture+sh-NC group, the acupuncture+sh-METTL14 group showed significantly decreased mRNA and protein expression of hippocampal METTL14 (P<0.01), and the upregulating effects of acupuncture on METTL3 and PTEN expression were reversed (P<0.01). Meanwhile, knockdown of METTL14 significantly inhibited the acupuncture-induced increase in PTEN m⁶A levels (P<0.01). Morphologically, knockdown of METTL14 attenuated the improvement of myelin structure by acupuncture, reversed the downregulation of MBP and upregulation of NF155 induced by acupuncture, and blocked the increase in dendritic spine density (P<0.05, P<0.01). ConclusionMETTL14 is a key molecule mediating the therapeutic effect of acupuncture at Neiguan. Acupuncture at Neiguan upregulates METTL14, thereby enhancing m⁶A methylation modification of PTEN mRNA to stabilize its expression, ultimately promoting myelin development and improving behavioral symptoms in ASD juvenile rats. This preliminarily reveals the modern biological connotation of “opening Xuanfu and dredging myelin”.

Exogenous harmful residues and endogenous toxic components are the main contents of safety analysis for animal traditional Chinese medicine. This review summarizes the inspection methods for exogenous harmful residues, as well as the research methods for the toxic effects and mechanisms of endogenous toxic components. The strategies for enhancing efficacy and reducing toxicity of toxic animal drugs and quality control, and prospects the development trend of safety analysis for animal drugs were also discussed. In the detection of exogenous harmful residues in animal drugs, traditional methods such as atomic absorption spectrometry and inductively coupled plasma mass spectrometry are widely used, and new methods such as high-resolution mass spectrometry and biochemical analysis are continuously developing. In the study of endogenous toxic components, the toxic components and mechanisms of some animal drugs including cantharidin and toad venom have been revealed through chemical composition analysis, toxicity tests and multiomics technologies, and some strategies for enhancing efficacy and reducing toxicity have been proposed based on this. In the future, it is necessary to strengthen multidisciplinary integration to innovate detection technologies, clarify toxic mechanisms to achieve efficacy enhancement and toxicity reduction, and improve the biosafety research system, so as to enhance the quality and safety of traditional Chinese medicine animal drugs and promote the internationalization process of traditional Chinese medicine.

Metabolic dysfunction-associated fatty liver disease （MAFLD） is the most prevalent chronic liver disease worldwide， with a complex pathogenesis. Mitochondria play a pivotal role in this disease process， and studies have confirmed that mitochondrial dysfunction can exacerbate metabolic disorders and induce innate immune imbalance， while mitochondrial DNA （mtDNA） is the core molecule mediating these two pathological effects. After the abnormal release of mtDNA， it can be recognized by intracellular pattern recognition receptors， which in turn triggers innate immune responses and causes tissue damage， forming a pathological pathway of “mtDNA release-immune activation-tissue damage”. Currently， there is a lack of systematic reviews summarizing the mechanism of action of this pathway in different stages of MAFLD and the intervention strategies targeting this pathway. This article systematically reviews the core molecular mechanism of this pathway， its pathological role in the development and progression of MAFLD， and the current intervention strategies targeting this mechanism， in order to provide a theoretical basis for analyzing the pathogenesis of MAFLD and developing novel therapeutic strategies.

The circadian clock plays a critical role in regulating various physiological processes, including gene expression, metabolic regulation, immune response, and the sleep-wake cycle in living organisms. Post-translational modifications (PTMs) are crucial regulatory mechanisms to maintain the precise oscillation of the circadian clock. By modulating the stability, activity, cell localization and protein-protein interactions of core clock proteins, PTMs enable these proteins to respond dynamically to environmental and intracellular changes, thereby sustaining the periodic oscillations of the circadian clock. Different types of PTMs exert their effects through distincting molecular mechanisms, collectively ensuring the proper function of the circadian system. This review systematically summarized several major types of PTMs, including phosphorylation, acetylation, ubiquitination, SUMOylation and oxidative modification, and overviewed their roles in regulating the core clock proteins and the associated pathways, with the goals of providing a theoretical foundation for the deeper understanding of clock mechanisms and the treatment of diseases associated with circadian disruption.
Protein Processing, Post-Translational/physiology* ; Circadian Rhythm/physiology* ; Humans ; Animals ; CLOCK Proteins/physiology* ; Circadian Clocks/physiology* ; Phosphorylation ; Acetylation ; Ubiquitination ; Sumoylation

The Baihe Dihuang Decoction(BDD) is a representative traditional Chinese medicine formula that has been used to treat depression. This study employed metabolomics and network pharmacology to investigate the mechanism of BDD in the treatment of depression. Fifty male Sprague-Dawley(SD) rats were randomly assigned to the normal control group, model group, fluoxetine group, and high-and low-dose BDD groups. A rat model of depression was established through chronic unpredictable mild stress(CUMS), and the behavioral changes were detected by forced swimming test and open field test. Metabolomics technology was used to analyze the metabolic profiles of serum and hippocampal tissue to screen differential metabolites and related metabolic pathways. Additionally, network pharmacology and molecular docking techniques were used to investigate the key targets and core active ingredients of BDD in improving metabolic abnormalities of depression. A "component-target-metabolite-pathway" regulatory network was constructed. BDD could significantly improve depressive-like behavior in CUMS rats and regulate 12 differential metabolites in serum and 27 differential metabolites in the hippocampus, involving tryptophan metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, alanine, aspartate, and glutamate metabolism, tyrosine metabolism, and purine metabolism. Verbascoside, isorbascoside, and regaloside B were the key active ingredients for improving metabolic abnormalities in depression. Epidermal growth factor receptor(EGFR), protooncogene tyrosine-protein kinase(SRC), glycogen synthase kinase 3β(GSK3β), and androgen receptor(AR) were the key core targets for improving metabolic abnormalities of depression. This study offered a preliminary insight into the mechanism of BDD in alleviating metabolic abnormalities of depression through network regulation, providing valuable guidance for its clinical use and subsequent research.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Rats, Sprague-Dawley ; Rats ; Metabolomics ; Depression/genetics* ; Antidepressive Agents/chemistry* ; Network Pharmacology ; Hippocampus/drug effects* ; Humans ; Molecular Docking Simulation ; Behavior, Animal/drug effects* ; Disease Models, Animal

Recent studies have shown that an imbalance in iron metabolism can affect the composition and microstructural changes of bone, disrupting bone homeostasis and leading to osteoporosis(OP). The imbalance in iron metabolism, along with its induced local abnormal microenvironment and cellular iron death, has become a new focal point in OP research, drawing increasing attention from the academic community regarding the regulation of iron metabolism to prevent and manage OP. From the perspective of traditional Chinese medicine(TCM), iron metabolism imbalance has potential connections to TCM theories regarding internal organs, as well as treatments aimed at tonifying the kidney, strengthening the spleen, and activating blood circulation. Evidence is continually emerging that TCMs and effective components that tonify the kidney, strengthen the spleen, and activate blood circulation can prevent and manage OP by regulating iron metabolism. This article analyzes the relationship between iron and bone, as well as the effects of TCM formulations on improving iron metabolism and influencing bone metabolism, from the perspectives of iron metabolism mechanisms and TCM interventions, aiming to broaden existing clinical strategies for prevention and treatment and inject new momentum into the field of OP as it moves into a new era.
Osteoporosis/drug therapy* ; Humans ; Iron/metabolism* ; Drugs, Chinese Herbal/pharmacology* ; Animals ; Medicine, Chinese Traditional ; Bone and Bones/drug effects*