International Journal of Molecular Medicine

Zhong, Yufei; Zou, Yunfei; Yang, Zhuoyuan; Wang, Junjun; Pan, Zezheng; Feng, Jiugeng

doi: N/Apmid: N/A

Ovarian granulosa cells (GCs), as key components of follicles, orchestrate follicular development and ovarian maturation through bidirectional communication with oocytes and through hormone synthesis. Their dysfunction substantially contributes to female infertility. Post‑translational modifications (PTMs) carry out pivotal roles in the regulation of ovarian physiology and pathology by modulating GC proliferation, differentiation, apoptosis and steroid hormone secretion. The present review seeks to summarize the current advances in canonical PTMs such as phosphorylation, methylation, acetylation and ubiquitination, as well as novel protein modifications such as SUMOylation and lactylation, particularly focusing on their roles in the proliferation, differentiation and apoptosis of GCs at the molecular level. Moreover, the present review explores how aberrant PTMs impair GC function, leading to follicular developmental disorders, and proposes that targeting PTM‑regulated signaling in GCs may provide novel therapeutic strategies for ovarian dysfunction. Collectively, the present review aims to provide insights into elucidating the etiology of infertility, and establishing a theoretical foundation for the development of PTM‑targeted reproductive interventions.

Ruan, Hang; Shen, Xiao-Yan; Liu, Shi-Yan; Li, Shu-Sheng

doi: N/Apmid: N/A

Sepsis‑induced vasoplegia, a life‑threatening complication of sepsis, has become a focal point of research endeavors aimed at determining its complex mechanisms. However, existing investigations predominantly focus on the role of endothelial cells (ECs) in sepsis, inadvertently dismissing the pivotal contribution of vascular smooth muscle cells (VSMCs). The present review highlights the frequently underappreciated role of VSMCs in sepsis‑induced vasodilation, and provides a comprehensive and systematic elucidation of the associated pathophysiological mechanisms. The current review examines the structural characteristics, localization, phenotypic transitions and heterogeneity of VSMCs, emphasizing their critical role in maintaining vascular homeostasis and regulating blood pressure. Subsequently, the review delves into the multifaceted effects of sepsis on VSMCs. Direct injury to VSMCs in sepsis occurs through pathogens. Additionally, the sepsis‑associated cytokine storm can activate key signaling pathways, such as the NF‑κB and p38 MAPK pathways, leading to a phenotypic shift in VSMCs from a contractile state to a synthetic state, thus enhancing their proliferative and migratory abilities. Concurrently, sepsis disrupts the intricate interaction between ECs and VSMCs, and interferes with calcium homeostasis, ultimately resulting in reduced vascular reactivity and abnormal vascular remodeling. Together, these mechanisms contribute to sepsis‑related vascular dysfunction and multiorgan failure. The in‑depth analysis of these processes in the present review offers novel insights into the pathological mechanisms of sepsis‑induced vasoplegia. The current study also provides a theoretical foundation for the development of clinical intervention strategies targeting VSMCs, with the potential to advance sepsis treatment strategies.

Wang, Enbo; Zhang, Haixiang; Wu, Dechao; Ali, Sadik; Ji, Xianglu

doi: N/Apmid: N/A

Secondary osteoarthritis, a degenerative joint disease, is often precipitated by well‑characterized etiological factors, with developmental dysplasia of the hip (DDH) emerging as a leading contributor. Despite its clinical importance, the intricate molecular and cellular cascades triggered by the biomechanical perturbations associated with DDH remain poorly understood. In the present study, a swaddling‑induced rat model of DDH was successfully developed, which recapitulated key pathological features including acetabular labral tears and cartilage degeneration. Through comprehensive mRNA‑sequencing analysis of acetabular cartilage samples from rats with DDH, a notable upregulation of dual‑specificity phosphatase 26 (DUSP26) was identified, a protein with previously unreported roles in joint homeostasis. Subsequently, in an <i>in vitro</i> inflammatory microenvironment induced by interleukin (IL)‑1β, adenovirus‑mediated overexpression of DUSP26 demonstrated marked chondroprotective effects. Specifically, this intervention led to a significant increase in the expression of type II collagen, a hallmark of healthy chondrocytes, while concurrently reducing the levels of catabolic markers such as type I collagen, TNF‑α and IL‑6. Reciprocally, adenovirus‑delivered short hairpin RNA‑mediated DUSP26 silencing exacerbated cartilage degradation, validating its protective function. Employing mass spectrometry‑based proteomics combined with genetic and pharmacological approaches, the underlying mechanism was elucidated: DUSP26 overexpression exerted its chondroprotective effects by dephosphorylating and inactivating histone deacetylase (HDAC)1, HDAC2 and HDAC8, thereby maintaining chondrocyte integrity. Collectively, the findings of the present study underscore DUSP26 as a promising therapeutic target for DDH‑associated osteoarthritis, offering novel mechanistic insights and laying the groundwork for the development of targeted interventions to mitigate secondary joint degeneration.

He, Guo-Qian; Liu, Guang-Yu; Xu, Wen-Ming; Liao, Hui-Juan; Liu, Xing-Hui; He, Guo-Lin

doi: N/Apmid: N/A

Following the publication of the above article, an interested reader drew to the authors' attention that, concerning the Transwell migration assay images shown in Fig. 6 on p. 287, the data panels for figure parts 6E (the DMSO experiment) and 6G (the pcDNA3.1+DMSO experiment) contained strikingly similar data, albeit with different sizing of the images, suggesting that these data had been derived from the same original source. Upon investigating this figure, the authors realized that this figure had inadvertently been assembled incorrectly: The data panel for the DMSO group in the HTR‑8/SVneo cell migration assay (Fig. 6E) had been duplicated from the correctly displayed pcDNA3.1+DMSO group panel. The revised version of Fig. 6, now showing the correct data panel for Fig. 6E, is shown on the next page. The authors confirm that the error associated with this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of <i>International Journal of Molecular Medicine</i> for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 44: 281-290, 2019; DOI: 10.3892/ijmm.2019.4175]

Pan, Liuzhu; Wen, Zongzhuang; Jin, Yi

doi: N/Apmid: N/A

Lipid droplets (LDs) are dynamic organelles that extend beyond lipid storage to regulate diverse aspects of reproductive physiology. In both mammals and <i>Caenorhabditis elegans</i>, LDs support gamete maturation, fertilization, embryogenesis and steroidogenesis by modulating lipid mobilization, signaling pathways, protein quality control and hormone production. The present review highlights the roles of LDs in oocytes, sperm, Sertoli and granulosa cells, embryonic stem cells and early embryos. Key regulatory molecules, including perilipins, adipose triglyceride lipase, Hormone‑Sensitive Lipase (HSL), Diacylglycerol O‑acyltransferases and seipin, as well as lipophagy, are discussed in the context of reproductive cell function. <i>C. elegans</i> demonstrates conserved genetic pathways linking LD metabolism with gamete quality and embryonic viability. The present review aimed to discuss emerging technologies such as lipidomics, high‑resolution imaging, Clustered Regularly Interspaced Short Palindromic Repeats screening and single‑cell sequencing that enable deeper investigation into LD dynamics. Finally, the present review aimed to examine how LD dysfunction contributes to reproductive disorders including infertility, polycystic ovary syndrome and metabolic syndrome. Understanding LD biology offers promising avenues for improving reproductive health and gamete and embryonic developmental potential.

Gao, Wen-Fan; Xu, Ya-Yun; Ge, Jin-Fang; Chen, Fei-Hu

doi: N/Apmid: N/A

Following the publication of the above article, an interested reader drew to the authors' attention that the control β‑actin western blots shown in Figs. 2C and 5A were strikingly similar, even though the experimental conditions reported in these figures were different. After having re‑examined the original data, the authors have realized that these western blots were inadvertently included in Fig. 2C erroneously. The revised version of Fig. 2, now incorporating the correct data for the β‑actin bands in Fig. 2C, is shown below. The authors confirm that the error associated with this figure did not have a significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of <i>International Journal of Molecular Medicine</i> for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 43: 1778‑1788, 2019; DOI: 10.3892/ijmm.2019.4085]

Li, Caizi; Tang, Xinglinzi; Luo, Xiaoru; Lai, Xin; Yang, Jing; Xu, Zheng; Muhetaer, Gulizeba; Xie, Yizi; Huang, Xiufang; Li, Hang

doi: N/Apmid: N/A

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disorder characterized by unexplained fibrosis and limited therapeutic options, highlighting the urgent need for innovative treatments. Hyaluronic acid (HA), which is upregulated in IPF and correlates with disease severity, plays an undefined role in its pathogenesis. Hyaluronic acid synthase 2 (HAS2), a key enzyme in HA production, has an unclear function in IPF progression, particularly regarding its involvement in macrophage polarization. Understanding this mechanism is essential for identifying novel therapeutic targets and developing effective drugs for IPF. The present study investigated the roles of HAS2 and HA in IPF and identified potential therapeutic agents. Transcriptomic analysis revealed HAS2 as a critical IPF‑associated gene in patient samples, bleomycin (BLM)‑induced mouse models, and transforming growth factor β1 (TGF‑β1)‑induced myofibroblasts. Single‑cell RNA sequencing further confirmed the fibroblast‑specific upregulation of HAS2 in fibrotic lungs. Experimental validation showed elevated HAS2 expression and HA accumulation in fibrosis models. HA facilitated macrophage M2 polarization and TGF‑β1 secretion through CD44‑dependent STAT6 activation, with CD44 inhibition blocking this effect. Knockdown of HAS2 in fibroblasts decreased HA release and impaired their ability to promote M2 polarization, suggesting that fibroblast‑derived HA drives this process. High‑throughput virtual screening, coupled with absorption, distribution, metabolism and excretion (ADME) profiling, identified orcinol glucoside (OG) as a potential HAS2 inhibitor, which was validated through surface plasmon resonance, cellular thermal shift assays, and molecular dynamics simulations. OG suppressed HA synthesis in TGF‑β1‑induced and HAS2‑overexpressing myofibroblasts in a dose‑dependent manner, inhibiting M2 polarization induction. <i>In vivo</i>, OG reduced collagen deposition, HA, and TGF‑β1 levels in BLM‑induced fibrotic mice. These findings established HAS2 as a central pathogenic factor in IPF and suggested OG as a promising therapeutic candidate, providing a novel approach for IPF treatment by targeting HA synthesis and macrophage polarization.

Li, Hanfei; Li, Yuxi; Zhang, Bo; Cheng, Wenhao; Ma, Guowei; Rong, Jin; Duan, Shiru; Feng, Di; Zhao, Tingting

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Diabetic kidney disease (DKD) is a microvascular complication of diabetes, characterized by region‑specific metabolic reprogramming that disrupts kidney function and markedly impairs patient prognosis. By enabling <i>in situ</i> visualization and analysis of metabolite distribution within kidney tissue, spatial metabolomics offers a unique advantage in detecting spatial heterogeneity in metabolic alterations, which is inaccessible through conventional metabolomics. This approach not only enhances the understanding of DKD pathophysiology but also provides a solid foundation for the development of precision nephrology strategies informed by spatial metabolite data. The present review discusses the fundamental workflows and spatial resolution capabilities of spatial metabolomics, summarizing the key metabolites involved in regional metabolic disruptions in multiple DKD animal models. Moreover, it highlights notable metabolites, including glucose, succinate, phosphatidylserine, lysophosphatidylglycerol, phosphatidylglycerol, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, taurine, glutamate, L‑carnitine, choline, adenosine monophosphate and guanosine monophosphate. The continued advancement of imaging technologies and data analysis methodologies is expected to further refine the spatial resolution and precision of spatial metabolomics, thereby facilitating its broader application in clinical practice.

Liang, Yongchun; Fan, Xinbiao; Geng, Xiaofei; Jia, Yunfeng; Shang, Wenyu; Sun, Xitong; Ge, Jun; Ye, Guijun; Zhu, Boyu; Zhang, Zheng; Kang, Yuxin; Shan, Xiaoyu; Zhang, Junping

doi:

Li, Wei; Wang, Wen-Hong; Song, Yi; Li, Xu-Jiong; Li, Yan; Wang, Xia; Tian, Ting-Ting; Huang, Xiao; Zhao, Li

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Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive cognitive decline and whose pathology is closely linked to cellular autophagy dysfunction. Autophagy is a key process involved in cell clearance. Impaired autophagy can drive neuronal damage and death related to AD pathology. Therefore, targeting autophagy dysfunction has emerged as a promising therapeutic strategy. Exercise, as a non‑pharmaceutical and low‑cost intervention method, can enhance autophagy activity and alleviate AD symptoms. However, the mechanism by which it regulates autophagy in AD remains unclear. The present review summarizes evidence that exercise acts as an effective early intervention. Exercise activates key cellular signaling pathways (mammalian target of rapamycin, sirtuin 1 and adiponectin receptor 1) and regulates microRNAs (small non‑coding RNAs) and irisin (a muscle hormone) to restore normal autophagy. The present review also explores the use of exercise combined with natural products for potential synergistic therapeutic effects. This review provides insights into developing new AD prevention and management strategies by detailing how exercise corrects AD‑related autophagy dysfunction.