Current molecular medicine最新文献

Rhythmicity is a characteristic feature of the inanimate universe. The organization of biological rhythms in time is an adaptation to the cyclical environmental changes brought on by the earth's rotation on its axis and around the sun. Circadian (L. Circa = "around or approximately"; diem = "a day") rhythms are biological responses to the geophysical light/dark (LD) cycle in which an organism adjusts to alterations in its internal physiology or external environment as a function of the time of day. Sleep has been considered a biological rhythm. Normal human sleep, an essential physiologic process, comprises two distinct phases: non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. A mature adult human's sleep/wake cycle displays a circadian rhythm with a ~24-hour cycle. According to the two-process model of sleep regulation, the human sleep/wake cycle is orchestrated by circadian and homeostatic processes. Sleep homeostasis (a sleep-dependent process) and circadian rhythm (a sleep-independent process) are two biological processes controlling the sleep/wake cycle. There are also ultradian (< 24-hour) rhythms, including the NREM-REM sleep cycle, which has been extensively studied. The clock and sleep genes both influence sleep. In this overview, we have reviewed the circadian genes and their role in regulating sleep. Besides, the gene expression and biological pathways associated with sleep and circadian rhythm-associated diseases also have been highlighted.

Unlocking the secrets of reproductive success in domestic animals requires a deep understanding of the molecular biology and immunology of spermatozoa, capacitation, fertilization, and conception. This review highlights the complex processes involved in spermatogenesis and sperm capacitation, including changes in membrane properties, signaling pathways, and the crucial acrosome reaction. The interaction with the zona pellucida in species-specific gamete recognition and binding is emphasized. The implications of fertilization defects for infertility and assisted reproduction are discussed, underscoring the challenges faced in breeding programs. The future directions for research in this field involve advancements in molecular techniques, understanding the immune regulation of spermatozoa, investigating environmental factors' impact, and integrating multi-omics approaches to enhance assisted reproduction techniques in domestic animals. This review contributes to our understanding of the intricate mechanisms underlying successful reproduction and provides insights into potential strategies for improving fertility outcomes in domestic animals.

Background: Keloid formation is characterized by excessive production of extracellular matrix, leading to dysregulated fibroproliferative collagen response. N6- methyl-adenosine (m6A) modification plays an essential role in this process.

Objective: Our objective in this study was to explore the mechanism of m6A methyltransferase KIAA1429 in keloid formation.

Methods: We examined the impact of m6A methyltransferase KIAA1429 on keloid formation using qRT-PCR, Western blot, immunofluorescence, Transwell migration assay, and MeRIP-qPCR.

Results: KIAA1429 was downregulated in keloid tissue. Overexpression of KIAA1429 suppressed fibroblast migration and reduced COL1A1 and α-SMA levels. Conversely, the knockdown of KIAA1429 promoted fibroblast migration and COL1A1 and α-SMA levels. Additionally, overexpression of KIAA1429 inhibited the TGF-β1/Smad pathway. Mechanistic experiments suggested that KIAA1429 regulated TGF-β1 m6A modification, maintained TGF-β1 mRNA stability, and participated in the regulation of keloid formation. Furthermore, TGF-β1 could reverse the effects of KIAA1429 overexpression on fibroblast migration and collagen deposition.

Conclusion: Taken together, our study suggested that KIAA1429 promoted keloid formation through the TGF-β1/Smad pathway, providing new insights for the treatment of keloid.

Background: Inflammation is the natural defense mechanism of the body in response to injury, infection, or other stimuli. Excessive or persistent inflammatory responses can lead to the development of inflammatory diseases. Therefore, elucidating the regulatory mechanisms of inflammatory cells is crucial for understanding the pathogenesis of such diseases and devising novel therapeutic approaches. Moreover, miR-144/451 plays an important role in erythroid maturity and tumour development. Herein, we have reviewed the regulatory role of miR-144/451 in inflammation.

Methods: Papers on miR-144, miR-451, and inflammation were retrieved from PubMed and Web of Science to be analysed and summarised.

Results: miR-144/451 plays a significant role in modulating inflammatory responses. Pro- and anti-inflammatory gene transcription is regulated by miR-144/451 binding to the 3' untranslated regions. Studies have shown that miR-451 inhibits the activation of various inflammatory cells, including macrophages, neutrophils, and T lymphocytes, thereby reducing the release of inflammatory mediators. However, miR-144 expression varies in different inflammatory diseases. miR-144 expression is downregulated in macrophages after induction by lipopolysaccharide, cysteine, or Mycobacterium tuberculosis, which promotes the secretion of inflammatory mediators; nonetheless, miR-144-3p overexpression in macrophages can aggravate atherosclerosis. Meanwhile, miR-144 overexpression prevents disruption of the lung endothelial cell barrier, whereas it exacerbates endothelial cell injury in Crohn's disease.

Conclusion: miR-144/451 may serve as a potential target for the treatment of inflammatory diseases.

Medical nanorobots and nanobots are at the forefront of therapy and diagnostics, potentially improving human health by enabling previously inaccessible treatments. This review explores critical issues concerning the design, components, signaling, structure, and roles of nanorobots and nanobots while elucidating the distinctions between microrobots and nanorobots or microrobotics and nanorobotics as well. By complementing traditional medical procedures, nanorobotic technology offers a rapid, safe, and potentially beneficial pathway toward early clinical applications. It finds numerous applications in both current and future pharmacological and medical advancements. The current and future applications of various nanorobots, such as DNA origami nanorobots, nucleic acid robots, microbivore nanorobots, respirocyte nanorobots, and orthodontic nanorobots, are briefly discussed. In the future, nanobots will likely be prominently featured in hospitals and pharmacies for individuals or specialized groups with specific needs. Continuous innovation and improvement of these technologies, addressing these technical challenges, will broadly advance research in micro/nanorobotics for medical diagnosis and treatment.

Background: Endometriosis (EM) is a gynecological disease characterized by the benign growth of endometrial tissue outside the uterus. Upregulation of neuronally expressed developmentally downregulated 4 (NEDD4) has been reported to accelerate endometrial cancer progression.

Objectives: We explored whether abnormal expression of NEDD4 is correlated with EM.

Methods: Endometrial tissue in patients without endometriosis was used to develop the original generation of endometrial stromal cells (ESCs). Different types of endometrial tissue of patients with endometriosis were used to measure the expression of NEDD4 by immunohistochemistry (IHC) and western blotting. Its biological functions in ESCs were investigated using a cell counting kit-8 assay, fluorescein diacetate (FDA) staining, and Transwell invasion assays. Additionally, its involvement in ferroptosis was assessed by measuring Fe2+, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) levels and the expression of ferroptosis markers.

Results: Compared with normal controls, NEDD4 levels were significantly elevated in the endometrial tissue of patients with EM. Furthermore, NEDD4 expression was higher in the ectopic endometrium than in the eutopic endometrium. NEDD4 knockdown reduced the viability and invasive capacity of ESCs, increased Fe2+, MDA, and ROS levels, and decreased GSH content. Further analysis revealed that NEDD4 knockdown promoted ferroptosis in ESCs by increasing the expression of prostaglandin-endoperoxide synthase 2 (PTGS2). As an E3 ubiquitin ligase, NEDD4 reduced PTGS2 protein levels by accelerating its ubiquitination and subsequent proteasomal degradation.

Conclusion: These findings suggest that inhibiting NEDD4 reduces ESC growth and invasion in EM by regulating PTGS2-dependent ferroptosis.

Introduction: Currently, Medullary Thyroid Carcinoma (MTC) is considered a kind of rare neuroendocrine tumor, and molecular-targeted drugs have previously been used for MTC treatment.

Method: However, the prognosis of MTC patients is still not significant. In the present work, we aimed to explore the antitumor activity of the molecularly targeted drug anlotinib in combination with radiofrequency ablation on MTC.

Result: The targets of anlotinib were clearly expressed in MTC tissue specimens, and the expression level of these factors was much higher in MTC clinical specimens than in nontumor tissues. At the same time, anlotinib or Radiofrequency Ablation (RFA) showed clear antitumor activity against the MTC cell line TT (TT cells) and the tumor tissue it formed. Anlotinib, in combination with RFA, significantly increased the antitumor activity of RFA.

Conclusion: These results indicated that the combination of anlotinib with radiofrequency ablation could be a promising therapeutic strategy for MTC treatment.

Background: Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease. According to Traditional Chinese Medicine (TCM) syndromes theory, moist heat arthralgia spasm syndrome is the most prevalent syndrome of RA patients in the active period. However, the mechanism of alteration of gut microbiota in RA with moist heat arthralgia spasm syndrome has not been reported until now.

Objective: This study focused on the alteration of gut microbiota in adjuvant-induced arthritis rats with moist heat arthralgia spasm syndrome, elaborated its regulation mechanism, and analyzed the associations between gut microbiota and microbial metabolites.

Methods: The disease-syndrome combination rat model of RA with moist heat arthralgia spasm syndrome was constructed with Adjuvant-Induced Arthritis (AIA) under damp-heat stimulating. Enzyme-Linked Immunosorbent Assay (ELISA) was used to measure serum biochemical indicators. Damages of ankle joints were observed using hematoxylin and eosin (H&E). 16 small ribosomal subunit RNA (16S rRNA) gene sequencing was conducted to assess the gut microbiota composition and function on feces from rats. Alterations in fecal metabolites profiling were evaluated by fecal metabolomics through Liquid Chromatography-Mass Spectrometry (LC-MS) and Gas Chromatography-Mass Spectrometry (GC-MS). Pearson correlation analysis was performed to explore the associations of altered gut microbiota and microbial metabolites in Model rats.

Results: The imbalance of gut microbiota in Model rats was accompanied by metabolic disorders. Lactobacillus, Prevotellaceae_NK3B31_group, Allobaculum, Prevotellaceae_UCG_001, Alloprevotella, and Dubosiella were found to be dominant genera in Model rats. In total, 357 metabolites were significantly altered in Model rats and predominantly enriched into fatty acid degradation and glycerophospholipid metabolism. Pearson correlation analysis showed that TNF-α and IL-1β were associated with Prevotellaceae_Ga6A1_group and 3R-hydroxy-docosan-5S-olide, alpha-N-(3-hydroxy-14-methyl-pentadecanoyl)-ornithine, 17-methyl-trans-4,5- methylenenona-decanoic acid, Semiplenamide F.

Conclusion: The key differential microbiota genera and differential microbial metabolites may become important targets for the treatment of RA and provide the theoretical basis for exploring the pathogenesis of RA.

Background and aim: Cancer-associated fibroblasts (CAFs), one of the most abundant stromal cell types in tumor microenvironment (TME), have been a potential target for cancer treatment such as lung cancer. However, the underlying mechanism by which CAFs promote lung cancer progression remains elusive.

Methods: We obtained primary CAFs, normal fibroblasts (NFs) and their exosomes, constructed protease nexin-1 (PN1) stably silenced or over-expressed CAFs cells using lentivirus. Bioinformatics was used to obtain the expression of PN1 in lung cancer and normal tissues, the relationship with overall survival, and the enriched pathways. The MTT assays and Transwell assays were performed to detect the proliferation, migration, and invasion abilities of lung cancer cells after treatments. Western blotting, qRT-PCR, immunohistochemistry, and xenograft models were used to illustrate how CAFs functions in lung cancer progression via exosomes.

Results: CAFs-derived exosomes, in which PN1 was higher expressed compared with NFs-derived ones, promoted effectively the proliferation, migration, and invasion of lung cancer cells A549 and H1975. Meanwhile, the expression of PN1 expressed higher in lung cancer tissues compared with normal ones, and was negatively associated with the overall survival rate of lung cancer patients. More importantly, over-expressing or silencing PN1 in A549 and H1975 could also promote or inhibit cell proliferation, migration, and invasion correspondingly. Furthermore, treated with PN1 over-expressed CAFs-derived exosomes, the lung cancer cells proliferation, migration, and invasion varied positively, and accompanied by activation of Toll-like and NF-κB signaling pathways. However, this phenomenon can be reversed by AN-3485, an antagonist of Toll-like pathway. Finally, over-expressing PN1 leads to an accelerated tumor growth by increasing the expression of proliferation biomarker Ki67 and activation of NF-κB signaling pathway in vivo.

Conclusions: CAFs promoted lung cancer progression by transferring PN1 and activating Toll-like/NF-κB signaling pathway via exosomes.

Background and objective: High morbidity, high mortality and poor prognosis of esophageal squamous cell carcinoma (ESCC) highlights the urgent need for novel therapeutic strategies against ESCC. The current study addresses the precise role of M2-like macrophages-derived CCL17 in ESCC progression and to thoroughly elucidate the intrinsic molecular mechanisms.

Methods: In this work, for functional experiments, Eca109 cells cultivated in M2-CM were treated with anti-IgG (50 μg/ml) or anti-CCL17 (50 μg/ml) to expound the tumorpromoting effects of M2-like macrophage-derived CCL17 in ESCC. Moreover, for rescue experiments, Eca109 cells were treated with CCL17 (50 ng/ml) and/or CCR4 antagonist AZD2098 (20 μM) to probe whether CCL17 could influence the malignant behaviors including migration, invasion and stemness of ESCC cells via activating CCR4/ERK/PD-L1 pathway.

Results: Markedly enhanced CCL17 secretion was observed in M2-like macrophages. CCL17 bound to CCR4 to activate ERK/PD-L1 signaling. M2-like macrophagesderived CCL17 facilitated ESCC cell migration and invasion and enhanced stemness characteristics of ESCC cells, which were partially reserved by AZD2098 treatment. The tumor-promoting effects of M2-like macrophages-derived CCL17 on ECSS was depended on the activation of CCR4/ERK/PD-L1 pathway.

Conclusion: To conclude, M2-like macrophages-derived CCL17 could facilitate ESCC cell migration and invasion and enhance stemness characteristics of ESCC cells via activating CCR4/ERK/PD-L1 signaling.