Pathology of pain and its implications for therapeutic interventions.

Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management is crucial for individuals suffering from pain. However, the current methods for pain assessment and treatment fall short of clinical needs. Benefiting from advances in neuroscience and biotechnology, the neuronal circuits and molecular mechanisms critically involved in pain modulation have been elucidated. These research achievements have incited progress in identifying new diagnostic and therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting the stage for the subsequent contents. The review next delves into the molecular mechanisms underlying pain disorders, including gene mutation, epigenetic modification, posttranslational modification, inflammasome, signaling pathways and microbiota. To better present a comprehensive view of pain research, two prominent issues, sexual dimorphism and pain comorbidities, are discussed in detail based on current findings. The status quo of pain evaluation and manipulation is summarized. A series of improved and innovative pain management strategies, such as gene therapy, monoclonal antibody, brain-computer interface and microbial intervention, are making strides towards clinical application. We highlight existing limitations and future directions for enhancing the quality of preclinical and clinical research. Efforts to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice, thereby improving pain management from bench to bedside.

The social hierarchical restrictions of Chinese verbs rapidly guide online thematic role assignment in comprehension.

The information about social hierarchical relationship has been intrinsically embedded into semantic restrictions of some Chinese verbs theoretically. For example, the Chinese verb ''(shanyang, support: provide for the needs and comfort of one's elders) only allows its Agent role to have a lower social status compared to the Patient role. However, whether this hierarchical restriction can be rapidly activated and how it impacts online thematic role assignment in reading remains to be seen. To answer this question, a 2 (Verb Type: hierarchical vs non-hierarchical verbs) × 2 (Social Hierarchy Sequence: match vs mismatch) design was constructed in the present study to investigate the interaction between the two factors. ERPs showed that hierarchical restriction violations evoked a stronger anterior negativity to the sentence-final noun (NP2). This effect was absent under two non-hierarchical conditions. To our knowledge, this study is the first to reveal that social hierarchical restrictions of Chinese hierarchical verbs can be rapidly available to guide online thematic role assignment and this process might be closely related to readers' thematic role knowledge.

Independent syntactic representation identified in left front-temporal cortex during Chinese sentence comprehension.

It has been well established that syntactic representation is independent of semantic representation in Indo-European languages, but it is unclear whether this is the case in Chinese. The present functional magnetic resonance imaging (fMRI) study adopted a syntactic priming paradigm to investigate the neural basis of Chinese syntactic representation. A passive sentence was preceded by either a passive or an active sentence without repeating a verb or a pattern of agent-patient animacy, thus constructing primed and unprimed sentence pairs based on sentence structure. The fMRI data were collected from 22 native Chinese speakers while they were reading the sentences. Priming-related activation suppression was found in the left temporal pole, left inferior frontal gyrus and left precentral gyrus. The results are the strongest neuroimaging evidence to date that syntactic representation is independent of semantic representation in Chinese, in line with Indo-European languages.

Role of circular RNAs and long non­coding RNAs in the clinical translation of gastric cancer (Review).

Gastric cancer (GC) is a malignancy with high incidence and mortality rates worldwide. It has a severe impact on patients diagnosed and on society. With the rapid development of bioinformatics and detection technologies, non­coding RNAs have been demonstrated to play important roles in gastric carcinogenesis, including circular RNAs (circRNAs) and long non­coding RNAs (lncRNAs). Previous studies have indicated that these two types of RNAs with notable characteristics can serve as promising biomarkers for clinical diagnosis and prognosis. The identification of relevant mechanisms has revealed the immense potential of circRNAs and lncRNAs in the treatment of GC. However, there are still numerous issues that need to be resolved. The present review focuses on the clinical translation of circRNAs and lncRNAs into GC. Important achievements and currently existing limitations in this field of research are summarized from recent studies. The present review also proposes serviceable suggestions for further development.

miR-1224-3p Promotes Breast Cancer Cell Proliferation and Migration through PGM5-Mediated Aerobic Glycolysis.

Metabolic reprogramming of aerobic glycolysis is a hallmark of cancer cells. Regulators of aerobic glycolysis have become targets for cancer diagnosis and therapy. However, the regulators of aerobic glycolysis in breast cancer development have not been well elucidated. Here, we show that the phosphoglucomutase (PGM) family member PGM5 promotes conversion of glucose-1-phosphate (G1P) into glucose-6-phosphate (G6P) and inhibits breast cancer cell proliferation and migration through regulating aerobic glycolysis. In breast cancer patients, PGM5 is significantly downregulated, and its low expression is a predictor of poor prognosis. MicroRNA-1224-3p (miR-1224-3p) inhibits the PGM5 level through directly targeting its 3'-untranslated region and suppresses PGM5-mediated breast cancer cell proliferation, migration, and glycolytic function. Moreover, the miR-1224-3p/PGM5 axis regulates the expression of cell cycle- and apoptosis-related genes and the markers of epithelial-mesenchymal transition (EMT), a process involved in migration and metastasis of cancer cells. Taken together, our results indicate that miR-1224-3p/PGM5 axis plays important roles in breast cancer cell proliferation, migration, and aerobic glycolysis and may be a potential target for breast cancer therapy.

Let-7a-5p inhibits triple-negative breast tumor growth and metastasis through GLUT12-mediated warburg effect.

Triple-negative breast cancer (TNBC) is known for its aggressive phenotype with limited treatment modalities and poor prognosis. The Warburg effect (aerobic glycolysis) is a hallmark of cancer that serves as a promising target for diagnosis and therapy. However, how aerobic glycolysis regulates TNBC remains largely unknown. Here, we show that the glucose transporter (GLUT) family member GLUT12 promotes TNBC tumor growth and metastasis in vitro and in vivo through regulating aerobic glycolysis. MicroRNA let-7a-5p, a tumor suppressor, inhibited GLUT12 expression by targeting its 3'-untranslated region, and suppressed GLUT12-mediated TNBC tumor growth, metastasis, and glycolytic function, including alterations of glucose uptake, lactate production, ATP generation, extracellular acidification rate, and oxygen consumption rate. Inhibiting aerobic glycolysis abolished the ability of let-7a-5p and GLUT12 to regulate TNBC cell proliferation, migration and invasion. In TNBC patients, GLUT12 was significantly upregulated, and let-7a-5p expression was inversely correlated with GLUT12 expression. High expression of let-7a-5p and GLUT12 predicted better and worse clinical outcomes, respectively. Taken together, our results indicate that the let-7a-5p/GLUT12 axis plays key roles in TNBC tumor growth and metastasis, and aerobic glycolysis, and is a potential target for TNBC treatment.

Snail promotes the generation of vascular endothelium by breast cancer cells.

A further understanding of tumor angiogenesis is urgently needed due to the limited therapeutic efficacy of anti-angiogenesis agents. However, the origin of endothelial cells (EC) in tumors remains widely elusive and controversial. Snail has been thoroughly elucidated as a master regulator of the epithelial-mesenchymal transition (EMT), but its role in endothelium generation is not yet established. In this study, we reported a new and unexpected function of Snail in endothelium generation by breast cancer cells. We showed that high Snail-expressing breast cancer cells isolated from patients showed more endothelium generated from these cells. Expression of Snail was positively correlated with endothelial markers in breast cancer patients. The ectopic expression of Snail induced endothelial marker expression, tube formation and DiI-AcLDL uptake of breast cancer cells in vitro, and enhanced tumor growth and microvessel density in vivo. Snail-mediated endothelium generation depended on VEGF and Sox2. Mechanistically, Snail promoted the expression of VEGF and Sox2 through recruiting the p300 activator complex to these promoters. We showed the dual function of Snail in tumor initiation and angiogenesis in vivo and in vitro through activation of Sox2 and VEGF, suggesting Snail may be an ideal target for cancer therapy.