Genes&Diseases

语种：英文出版周期：双月刊

E-ISSN：2352-3042P-ISSN：2352-4820

主管单位：重庆市教育委员会主办单位：重庆医科大学

Genes and Diseases是本由重庆医科大学于2014年创办的双月刊，也是国内第一本分子医学与转化医学相结合的全英文综合期刊，并入选“中国科技期刊卓越行动计划”高起点新刊项目。

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The authors regret that in Figure 3C, the Western Blot (WB) image representing GAPDH levels was mistakenly chosen as the same image for ERK (indicated by the red dotted-line rectangle). We have attached the original WB strip for GAPDH to demonstrate that this was an unintentional error in image selection. Additionally, we noticed that the Transwell images in the two upper panels of the right column in Figure 4J are misleading due to errors in image selection. We have attached the original data to show that this was also an unintentional error. We assure you that these two corrections do not alter the scientific conclusion of the article.

The authors regret that some data errors were made in “Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression” at Figure 5F for the colony formation of MNNG/HOS cells with si-NOTCH3 and 5G for the tranwell assay of U2OS cells with si-NOCTH3. Correction and supplementation to Figure 5. The author used confusing experimental data and did not notice these errors when submitting the original manuscript. Here, the authors made the latest corrections to the data of the batch of U2OS cells and MNNG/HOS cells transfected with si-NOTCH3. The authors confirm that this correction will not alter the conclusions in the original manuscript.

Introducing article numbering to Genes & DiseasesWithin the publishing industry, article numbering has emerged as an easy and efficient way to cite journal articles. Article numbering has already been successfully rolled out to Elsevier’s multidisciplinary open access journal Heliyon, as well as more than 1600 other journals, and has been well received by the academic community. Based on that positive feedback, we are now pleased to introduce article numbering to Genes & Diseases from 3rd issue of 2024.

There are few tumor cell subpopulations with stem cell characteristics in tumor tissue, defined as cancer stem cells (CSCs) or cancer stem-like cells (CSLCs), which can reconstruct neoplasms with malignant biological behaviors such as invasiveness via self-renewal and unlimited generation. The microenvironment that CSCs depend on consists of various cellular components and corresponding medium components. Among these factors existing at a variety of levels and forms, cytokine networks and numerous signal pathways play an important role in signaling transduction. These factors promote or maintain cancer cell stemness, and participate in cancer recurrence, metastasis, and resistance. This review aims to summarize the recent molecular data concerning the multilayered relationship between CSCs and CSC-favorable microenvironments. We also discuss the therapeutic implications of targeting this synergistic interplay, hoping to give an insight into targeting cancer cell stemness for tumor therapy and prognosis.

Long non-coding RNAs (lncRNAs) are non-coding RNAs longer than 200 nucleotides with dynamic regulatory functions. They interact with a wide range of molecules such as DNA, RNA, and proteins to modulate diverse cellular functions through several mechanisms and, if deregulated, they can lead to cancer development and progression. Recently, it has been described that lncRNAs are susceptible to form gene fusions with mRNAs or other lncRNAs, breaking the paradigm of gene fusions consisting mainly of protein-coding genes. However, their biological significance in the tumor phenotype is still uncertain. Therefore, their recent identification opens a new line of research to study their biological role in tumorigenesis, and their potential as biomarkers with clinical relevance or as therapeutic targets. The present study aimed to review the lncRNA fusions identified so far and to know which of them have been associated with a potential function. We address the current challenges to deepen their study as well as the reasons why they represent a future therapeutic window in cancer.

Liver diseases are worldwide problems closely associated with various stresses, such as endoplasmic reticulum stress. The exact interplay between stress and liver diseases remains unclear. Autophagy plays an essential role in maintaining homeostasis, and recent studies indicate tight crosstalk between stress and autophagy in liver diseases. Once the balance between damage and autophagy is broken, autophagy can no longer resist injury or maintain homeostasis. In recent years, FGF21 (fibroblast growth factor 21)-induced autophagy has attracted much attention. FGF21 is regarded as a stress hormone and can be up-regulated by an abundance of signaling pathways in response to stress. Also, increased FGF21 activates autophagy by a complicated signaling network in which mTOR plays a pivotal role. This review summarizes the mechanism of FGF21-mediated autophagy and its derived application in the defense of stress in liver diseases and offers a glimpse into its promising prospect in future clinical practice.

Fibroblast growth factor 21 (FGF21) was originally identified as an important metabolic regulator which plays a crucial physiological role in regulating a variety of metabolic parameters through the metabolic network. As a novel multifunctional endocrine growth factor, the role of FGF21 in the metabolic network warrants extensive exploration. This insight was obtained from the observation that the FGF21-dependent mechanism that regulates lipid metabolism, glycogen transformation, and biological effectiveness occurs through the coordinated participation of the liver, adipose tissue, central nervous system, and sympathetic nerves. This review focuses on the role of FGF21-uncoupling protein 1 (UCP1) signaling in lipid metabolism and how FGF21 alleviates non-alcoholic fatty liver disease (NAFLD). Additionally, this review reveals the mechanism by which FGF21 governs glucolipid metabolism. Recent research on the role of FGF21 in the metabolic network has mostly focused on the crucial pathway of glucolipid metabolism. FGF21 has been shown to have multiple regulatory roles in the metabolic network. Since an adequate understanding of the concrete regulatory pathways of FGF21 in the metabolic network has not been attained, this review sheds new light on the metabolic mechanisms of FGF21, explores how FGF21 engages different tissues and organs, and lays a theoretical foundation for future in-depth research on FGF21-targeted treatment of metabolic diseases.

Long COVID, also known for post-acute sequelae of COVID-19, describes the people who have the signs and symptoms that continue or develop after the acute COVID-19 phase. Long COVID patients suffer from an inflammation or host responses towards the virus approximately 4 weeks after initial infection with the SARS CoV-2 virus and continue for an uncharacterized duration. Anyone infected with COVID-19 before could experience long-COVID conditions, including the patients who were infected with SARS CoV-2 virus confirmed by tests and those who never knew they had an infection early. People with long COVID may experience health problems from different types and combinations of symptoms over time, such as fatigue, dyspnea, cognitive impairments, and gastrointestinal (GI) symptoms (e.g., nausea, vomiting, diarrhea, decreased or loss of appetite, abdominal pain, and dysgeusia). The critical role of the microbiome in these GI symptoms and long COVID were reported in clinical patients and experimental models. Here, we provide an overall view of the critical role of the GI tract and microbiome in the development of long COVID, including the clinical GI symptoms in patients, dysbiosis, viral–microbiome interactions, barrier function, and inflammatory bowel disease patients with long COVID. We highlight the potential mechanisms and possible treatment based on GI health and microbiome. Finally, we discuss challenges and future direction in the long COVID clinic and research.

Mitochondrial diseases are a heterogeneous group of inherited disorders characterized by mitochondrial dysfunction, and these diseases are often severe or even fatal. Mitochondrial diseases are often caused by mitochondrial DNA mutations. Currently, there is no curative treatment for patients with pathogenic mitochondrial DNA mutations. With the rapid development of traditional gene editing technologies, such as zinc finger nucleases and transcription activator-like effector nucleases methods, there has been a search for a mitochondrial gene editing technology that can edit mutated mitochondrial DNA; however, there are still some problems hindering the application of these methods. The discovery of the DddA-derived cytosine base editor has provided hope for mitochondrial gene editing. In this paper, we will review the progress in the research on several mitochondrial gene editing technologies with the hope that this review will be useful for further research on mitochondrial gene editing technologies to optimize the treatment of mitochondrial diseases in the future.

The liver is an important metabolic and detoxification organ and hence demands a large amount of energy, which is mainly produced by the mitochondria. Liver tissues of patients with alcohol-related or non-alcohol-related liver diseases contain ultrastructural mitochondrial lesions, mitochondrial DNA damage, disturbed mitochondrial dynamics, and compromised ATP production. Overproduction of mitochondrial reactive oxygen species induces oxidative damage to mitochondrial proteins and mitochondrial DNA, decreases mitochondrial membrane potential, triggers hepatocyte inflammation, and promotes programmed cell death, all of which impair liver function. Mitochondrial DNA may be a potential novel non-invasive biomarker of the risk of progression to liver cirrhosis and hepatocellular carcinoma in patients infected with the hepatitis B virus. We herein present a review of the mechanisms of mitochondrial dysfunction in the development of acute liver injury and chronic liver diseases, such as hepatocellular carcinoma, viral hepatitis, drug-induced liver injury, alcoholic liver disease, and non-alcoholic fatty liver disease. This review also discusses mitochondrion-centric therapies for treating liver diseases.

Osteoarthritis and psoriasis arthritis are two degenerative forms of arthritis that share similar yet also different manifestations at the histological, cellular, and clinical levels. Rheumatologists have marked them as two entirely distinct arthropathies. Given recent discoveries in disease initiation and progression, potential mechanisms, cellular signaling pathways, and ongoing clinical therapeutics, there are now more opportunities for discovering osteoarthritis drugs. This review summarized the osteoarthritis and psoriasis arthritis signaling pathways, crosstalk between BMP, WNT, TGF-β, VEGF, TLR, and FGF signaling pathways, biomarkers, and anatomical pathologies. Through bench research, we demonstrated that regenerative medicine is a promising alternative for treating osteoarthritis by highlighting significant scientific discoveries on entheses, multiple signaling blockers, and novel molecules such as immunoglobulin new antigen receptors targeted for potential drug evaluation. Furthermore, we offered valuable therapeutic approaches with a multidisciplinary strategy to treat patients with osteoarthritis or psoriasis arthritis in the coming future in the clinic.

Metabolomics as a research field and a set of techniques is to study the entire small molecules in biological samples. Metabolomics is emerging as a powerful tool generally for precision medicine. Particularly, integration of microbiome and metabolome has revealed the mechanism and functionality of microbiome in human health and disease. However, metabolomics data are very complicated. Preprocessing/pretreating and normalizing procedures on metabolomics data are usually required before statistical analysis. In this review article, we comprehensively review various methods that are used to preprocess and pretreat metabolomics data, including MS-based data and NMR -based data preprocessing, dealing with zero and/or missing values and detecting outliers, data normalization, data centering and scaling, data transformation. We discuss the advantages and limitations of each method. The choice for a suitable preprocessing method is determined by the biological hypothesis, the characteristics of the data set, and the selected statistical data analysis method. We then provide the perspective of their applications in the microbiome and metabolome research.

Atherosclerotic cardiovascular disease and its complications are a high-incidence disease worldwide. Numerous studies have shown that blood flow shear has a huge impact on the function of vascular endothelial cells, and it plays an important role in gene regulation of pro-inflammatory, pro-thrombotic, pro-oxidative stress, and cell permeability. Many important endothelial cell mechanosensitive genes have been discovered, including KLK10, CCN gene family, NRP2, YAP, TAZ, HIF-1α, NF-κB, FOS, JUN, TFEB, KLF2/KLF4, NRF2, and ID1. Some of them have been intensively studied, whereas the relevant regulatory mechanism of other genes remains unclear. Focusing on these mechanosensitive genes will provide new strategies for therapeutic intervention in atherosclerotic vascular disease. Thus, this article reviews the mechanosensitive genes affecting vascular endothelial cells, including classical pathways and some newly screened genes, and summarizes the latest research progress on their roles in the pathogenesis of atherosclerosis to reveal effective therapeutic targets of drugs and provide new insights for anti-atherosclerosis.

The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial–mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.

This correspondence to Gene & Diseases calls attention to the controversy between proponents of genetic modification in carcinogenesis and supporters of non-mutational oncogenesis. Data from molecular cancer research and findings from evolutionary cancer cell biology support the latter claim and provide no rationale for the mutational origin of sporadic cancers. It is more conceivable that the general susceptibility of asymmetric cell division (ACD) phenotypes to oxygen leads to irreparable DNA defects and dysregulated defective symmetric cell division (DSCD) phenotypes, and their repair through an ancient polyploid MGRS (multinucleated giant repair structures) repair mechanism initiates oncogenesis. This is reported in detail in the following lines.

One of the bottlenecks in the clinical treatment of small cell lung cancer (SCLC) is its susceptibility to multidrug resistance. While SCLC is sensitive to platinum-based chemotherapy at the initial stage of treatment, it can rapidly become drug-resistant, allowing tumor growth to accelerate. A significant decrease in drug sensitivity after recurrence and multidrug resistance can seriously interfere with the effectiveness of treatment, making sensitivity maintenance one of the urgent challenges to be solved. Therefore, discovering prognostic markers for cisplatin chemotherapy and understanding the mechanisms of cisplatin resistance have great practical significance for improving the outcomes of SCLC patients. CD209, also known as DC-SIGN, belongs to the C-type lectin superfamily and is mainly expressed in dendritic cells. In the past few years, growing evidence has shown that CD209 can also combine with Lewis antigens (which are highly expressed in cancer) and promote the process of T-cell presentation, thus initiating a series of immune cascades.1 Damaging this process, which thus helps tumors evade the immune response, may be one of the possible mechanisms of chemotherapy resistance. However, controversy has been raised about the role of the CD209 signaling pathway in different types of cancer. In lung cancer, increased expression of CD209 is associated with better survival, while in colorectal cancer, the opposite trend is observed, with CD209 promoting cancer progression.1,2 In this study, we explored the relationships between the activation of the CD209 signaling pathway with the efficacy of cisplatin and prognosis in SCLC patients.

Germline genetics of high penetrance such as BRCA genes, mutations might be sufficient for carcinogenesis, but this only explains fewer than 10% of cancers. We assume that most cancers are the result of germline mutations of low to moderate penetrance, combined with acquired mutations due to external carcinogenic stressors. With their accumulation over time, aging is associated with an increased risk of multiple cancer development in a given individual. For decades, germline genetics have been based on familial linkage studies enabling most high-penetrance genes to be identified. More recently, population-wide studies have led to the identification of considerable numbers of polymorphisms associated with cancer risk. However, most of them are of unknown functional value, thus limiting their translational application.

Major depressive disorder (MDD) and type 2 diabetes (T2D) are two common complex multifactorial disorders that share several genetic and environmental risk factors such as hypercortisolism and related genes' risk variants within the stress response and the neuroendocrine hypothalamic-pituitary axis. Under stress, the pituitary gland releases prolactin (PRL), whose effects are pleiotropic and include mood control and insulin secretion from the beta cells.1 Variations in the prolactin receptor (PRLR) gene are associated in rodent models with stress level, depression-like behavior,2 and hepatic insulin sensitivity3 and in humans with maternal glucose homeostasis and gestational diabetes.4 Furthermore, prolonged breastfeeding has been associated with reduced incidence of T2D, potentially related to PRL action. To our knowledge, no studies are reporting PRLR as a risk gene for MDD or T2D. Therefore, we aimed to investigate if the PRLR gene encoding for the PRLR plays a role in the familial comorbidity of MDD and T2D.

Glutamine is an important α-amino acid that provides carbon and nitrogen sources for the biosynthesis of nucleotides, proteins, and lipids. It also generates metabolites that fuel the tricarboxylic acid cycle and maintain intracellular redox balances. Malignant cells have a heightened metabolic dependence on glutamine to support incessant tumor growth and mitigate tumor microenvironmental stresses including hypoxia, nutrient depletion, and oxidative stress. Somatic sequence mutations including MYC, TP53, Ras, NRF2/KEAP1, and PIK3CA, not only transform tumor cells but also alter their metabolic states, leading to an increased reliance on glutamine.1 Consequently, targeting the abnormal metabolism of tumor cells may be an effective strategy to starve cancer cells and induce anti-tumor effects. In this report, we highlight two recent papers that present significant advancements in the field of targeting glutamine metabolic pathways.1,2 Specifically, both research articles report the development of a promising glutamine antimetabolite and the potency of its analog in modulating the immune landscape. These findings hold great promise for further exploration and development of novel therapeutic agents that leverage the altered metabolism to treat different types of cancer.

Glioma is a common tumor originating in the brain that has a high mortality rate. Temozolomide (TMZ) is the first-line treatment for high-grade gliomas. However, a large proportion of gliomas are resistant to TMZ, posing a great challenge to their treatment. In the study, the specific functions and mechanism(s) by which cortistatin (CORT) regulates TMZ resistance and glioma progression were evaluated. The decreased expression of CORT was detected in glioma tissues, and highly expressed CORT was associated with a better survival rate in patients with glioma. CORT overexpression notably decreased the capacity of glioma cells to proliferate and migrate in vitro and to form tumors in vivo. CORT overexpression also markedly suppressed the viability and enhanced the apoptosis of TMZ-resistant U251 cells by regulating MGMT, p21, and Puma expression. Importantly, CORT overexpression reduced the resistance of gliomas to TMZ in vivo. CORT expression was negatively correlated with MGMT expression in both glioma tissues and cells, and it was found that CORT inhibited NF-κB pathway activation in glioma cells, thereby inhibiting MGMT expression. In conclusion, CORT regulates glioma cell growth, migration, apoptosis, and TMZ resistance by weakening the activity of NF-κB/p65 and thereby regulating MGMT expression. The CORT/NF-κB/MGMT axis might be regarded as a molecular mechanism contributing to the resistance of glioma to TMZ. Our data also suggest that CORT regulates the viability and metastatic potential of glioma cells, independent of its effects on TMZ resistance, providing evidence of novel therapeutic targets for glioma that should be evaluated in further studies.

Capsular contracture is a prevalent and severe complication that affects the postoperative outcomes of patients who receive silicone breast implants. At present, prosthesis replacement is the major treatment for capsular contracture after both breast augmentation procedures and breast reconstruction following breast cancer surgery. However, the mechanism(s) underlying breast capsular contracture remains unclear. This study aimed to identify the biological features of breast capsular contracture and reveal the potential underlying mechanism using RNA sequencing. Sample tissues from 12 female patients (15 breast capsules) were divided into low capsular contracture (LCC) and high capsular contracture (HCC) groups based on the Baker grades. Subsequently, 41 lipid metabolism-related genes were identified through enrichment analysis, and three of these genes were identified as candidate genes by SVM-RFE and LASSO algorithms. We then compared the proportions of the 22 types of immune cells between the LCC and HCC groups using a CIBERSORT analysis and explored the correlation between the candidate hub features and immune cells. Notably, PRKAR2B was positively correlated with the differentially clustered immune cells, which were M1 macrophages and follicular helper T cells (area under the ROC = 0.786). In addition, the expression of PRKAR2B at the mRNA or protein level was lower in the HCC group than in the LCC group. Potential molecular mechanisms were identified based on the expression levels in the high and low PRKAR2B groups. Our findings indicate that PRKAR2B is a novel diagnostic biomarker for breast capsular contracture and might also influence the grade and progression of capsular contracture.

Osteosarcoma is a differentiation-deficient disease, and despite the unique advantages and great potential of differentiation therapy, there are only a few known differentiation inducers, and little research has been done on their targets. Cell differentiation is associated with an increase in mitochondrial content and activity. The metabolism of some tumor cells is characterized by impaired oxidative phosphorylation, as well as up-regulation of aerobic glycolysis and pentose phosphate pathways. Leucine-containing zipper and EF-hand transmembrane protein 1 (LETM1) is involved in the maintenance of mitochondrial morphology and is closely associated with tumorigenesis and progression, as well as cancer cell stemness. We found that MG63 and 143B osteosarcoma cells overexpress LETM1 and exhibit abnormalities in mitochondrial structure and function. Knockdown of LETM1 partially restored the mitochondrial structure and function, inhibited the pentose phosphate pathway, promoted oxidative phosphorylation, and led to osteogenic differentiation. It also inhibited spheroid cell formation, proliferation, migration, and invasion in an in vitro model. When LETM1 was knocked down in vivo, there was reduced tumor formation and lung metastasis. These data suggest that mitochondria are aberrant in LETM1-overexpressing osteosarcoma cells, and knockdown of LETM1 partially restores the mitochondrial structure and function, inhibits the pentose phosphate pathway, promotes oxidative phosphorylation, and increases osteogenic differentiation, thereby reducing malignant biological behavior of the cells.

Bone defects and non-union are prevalent in clinical orthopedy, and the outcomes of current treatments are often suboptimal. Bone tissue engineering offers a promising approach to treating these conditions effectively. Bone morphogenetic protein 9 (BMP9) can commit mesenchymal stem cells to osteogenic lineage, and a knowledge of the underlying mechanisms may help advance the field of bone tissue engineering. Leucine-rich repeats containing G protein-coupled receptor 4 (LGR4), a member of G protein-coupled receptors, is essential for modulating bone development. This study is aimed at investigating the impact of LGR4 on BMP9-induced osteogenesis in mesenchymal stem cells as well as the underlying mechanisms. Bone marrow stromal cells from BMP9-knockout mice exhibited diminished LGR4 expression, and exogenous LGR4 clearly restored the impaired osteogenic potency of the bone marrow stromal cells. Furthermore, LGR4 expression was increased by BMP9 in C3H10T1/2 cells. LGR4 augmented the benefits of BMP9-induced osteogenic markers and bone formation, whereas LGR4 inhibition restricted these effects. Meanwhile, the BMP9-induced lipogenic markers were increased by LGR4 inhibition. The protein levels of Raptor and p-Stat3 were elevated by BMP9. Raptor knockdown or p-Stat3 suppression attenuated the osteoblastic markers and LGR4 expression brought on by BMP9. LGR4 significantly reversed the blocking effect of Raptor knockdown or p-Stat3 suppression on the BMP9-induced osteoblastic markers. Raptor interacts with p-Stat3, and p-Stat3 activates the LGR4 promoter activity. In conclusion, LGR4 boosts BMP9 osteoblastic potency in mesenchymal stem cells, and BMP9 may up-regulate LGR4 via the mTORC1/Stat3 signal activation.

Furin is a pro-protein convertase that moves between the trans-Golgi network and cell surface in the secretory pathway. We have previously reported that cerebral overexpression of furin promotes cognitive functions in mice. Here, by generating the brain-specific furin conditional knockout (cKO) mice, we investigated the role of furin in brain development. We found that furin deficiency caused early death and growth retardation. Magnetic resonance imaging showed severe hydrocephalus. In the brain of furin cKO mice, impaired ciliogenesis and the derangement of microtubule structures appeared along with the down-regulated expression of RAB28, a ciliary vesicle protein. In line with the widespread neuronal loss, ependymal cell layers were damaged. Further proteomics analysis revealed that cell adhesion molecules including astrocyte-enriched ITGB8 and BCAR1 were altered in furin cKO mice; and astrocyte overgrowth was accompanied by the reduced expression of SOX9, indicating a disrupted differentiation into ependymal cells. Together, whereas alteration of RAB28 expression correlated with the role of vesicle trafficking in ciliogenesis, dysfunctional astrocytes might be involved in ependymal damage contributing to hydrocephalus in furin cKO mice. The structural and molecular alterations provided a clue for further studying the potential mechanisms of furin.

Ovarian cancer is the tumor with the highest mortality among gynecological malignancies. Studies have confirmed that paclitaxel chemoresistance is associated with increased infiltration of tumor-associated macrophages (TAMs) in the microenvironment. Colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) plays a key role in regulating the number and differentiation of macrophages in certain solid tumors. There are few reports on the effects of targeted inhibition of CSF-1R in combination with chemotherapy on ovarian cancer and the tumor microenvironment. Here, we explored the antitumor efficacy and possible mechanisms of the CSF − 1R inhibitor pexidartinib (PLX3397) when combined with the first-line chemotherapeutic agent paclitaxel in the treatment of ovarian cancer. We found that CSF-1R is highly expressed in ovarian cancer cells and correlates with poor prognosis. Treatment by PLX3397 in combination with paclitaxel significantly inhibited the growth of ovarian cancer both in vitro and in vivo. Blockade of CSF-1R altered the macrophage phenotype and reprogrammed the immunosuppressive cell population in the tumor microenvironment.

MYBL2 (MYB proto-oncogene like 2) is an emerging prognostic marker for malignant tumors, and its potential role in osteosarcoma and its relationship with immune infiltration in pan-cancer is yet to be elucidated. We constructed a transcription factor activity profile of osteosarcoma using the single-cell regulatory network inference algorithm based on single-cell RNA sequencing data obtained from the Gene Expression Omnibus. Subsequently, we calculated the extent of MYBL2 activation in malignant proliferative osteoblasts. We also explored the association between MYBL2 and chemotherapy resistance in osteosarcoma. Furthermore, we systematically correlated MYBL2 with immunological signatures in the tumor microenvironment in pan-cancer, including immune cell infiltration, immune checkpoints, and tumor immunotherapy prognosis. Finally, we developed and validated a risk score (MRGS), derived an osteosarcoma risk score nomogram based on MRGS, and tested its ability to predict prognosis. MYBL2 and gene enrichment analyses in osteosarcoma and pan-cancer revealed that MYBL2 was positively correlated with cell proliferation and tumor immune pathways. MYBL2 expression positively correlated with SLC19A1 in pan-cancer and osteosarcoma cell lines. Pan-cancer immune infiltration analysis revealed that MYBL2 was correlated with myeloid-derived suppressor cells, Th2 cell infiltration, CD276, RELT gene expression, and tumor mutation burden. In summary, MYBL2 regulates proliferation, progression, and immune infiltration in osteosarcoma and pan-cancer. Therefore, we found that MYBL2 could be used as a potential marker for predicting the osteosarcoma prognosis. Patients with osteosarcoma and high MYBL2 expression are theoretically more sensitive to methotrexate. An osteosarcoma prognostic nomogram can provide new ideas in the search for osteosarcoma prognostic markers.

The factors that determine fibrosis progression or normal tissue repair are largely unknown. We previously demonstrated that autophagy inhibition-mediated epithelial–mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signaling. Here, we report that liver kinase B1 (LKB1) inactivation in ATII cells inhibits autophagy and induces EMT as a consequence. In IPF lungs, this is caused by the down-regulation of CAB39L, a key subunit within the LKB1 complex. 3D co-cultures of ATII cells and MRC5 lung fibroblasts coupled with RNA sequencing (RNA-seq) confirmed that paracrine signaling between LKB1-depleted ATII cells and fibroblasts augmented myofibroblast differentiation. Together, these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATII cells and contribute to fibrosis via aberrant epithelial–fibroblast crosstalk.

The adenosine monophosphate (AMP)-activated protein kinase (AMPK) sits at a central node in the regulation of energy metabolism and tumor progression. AMPK is best known to sense high cellular ADP or AMP levels, which indicate the depletion of energy stores. Previous studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic cancer. In this study, we report that AMPK is also highly sensitive to extracellular matrix (ECM) stiffness. We found that AMPK is activated in cells when cultured under low ECM stiffness conditions and is functionally required for the metabolic switch induced by ECM stiffness. This regulation of AMPK requires the Hippo kinases but not LKB1/CaMKKβ. Hippo kinases directly phosphorylate AMPKα at Thr172 to activate AMPK at low ECM stiffness. Furthermore, we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma (PDAC) with high ECM stiffness and is associated with a poor survival outcome. The activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC growth. Together, these findings establish a novel model for AMPK regulation by the mechanical properties of ECMs and provide a rationale for simultaneously targeting the ECM stiffness–Hippo kinases–AMPK signaling and low glucose–LKB1–AMPK signaling pathways as an effective therapeutic strategy against PDAC.

Epilepsy, one of the most common neurological disorders, is characterized by spontaneous recurrent seizures. Temporal lobe epilepsy (TLE) is one of the most common medically intractable seizure disorders. Traf2-and NcK-interacting kinase (TNIK) has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders, but its role in epilepsy remains unclear. In this study, we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpine-induced rat model of epilepsy by western blotting, immunofluorescence, and immunohistochemistry. A pentylenetetrazole (PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of epilepsy. Coimmunoprecipitation (Co-IP)/mass spectrometry (MS) was used to identify the potential mechanism. Through Co-IP, we detected and confirmed the main potential TNIK interactors. Subcellular fractionation was used to establish the effect of NCB-0846 on the expression of the main interactors in postsynaptic density (PSD) fractions. We found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with controls. NCB-0846 delayed kindling progression and decreased seizure severity. Co-IP/MS identified 63 candidate TNIK interactors in rat hippocampi, notably CaMKII. Co-IP showed that TNIK might correlate with endogenous GRIA1, SYN2, PSD-95, CaMKIV, GABRG1, and GABRG2. In addition, the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ kindling. Our results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target.

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are two disease conditions for which obesity is a risk factor.1 Due to the close relationship between the three pathologies, researchers frequently use the same mouse models to identify the underlying processes of obesity, NAFLD, and T2DM. For instance, leptin (Lep)-null (ob/ob) and leptin receptor (Lepr)-deficient (db/db) mice spontaneously develop NAFLD and show different phenotypes of extreme obesity and diabetes, respectively.2,3 Creating and applying more pertinent models to analyze disease-specific pathways is necessary. Interestingly, wild-derived WSB/Eij mice are resistant to obesity and developing NAFLD. To comprehend the reason for this resistance and the potential role of the Lepr mutation in the development of obesity, we created the congenic strain WSB-db. These congenic WSB-db mice developed mild obesity and hyperglycemia without hepatic steatosis/NAFLD and renal consequences. Various differentially expressed genes (DEGs) were discovered in congenic WSB-db compared to its parent strains (WSB/Eij and B6-db), which may explain the different susceptibility to NAFLD. Thus, the congenic WSB-db mice may be a suitable model to separate the genes and mechanisms crucial to obesity and NAFLD.

Alagille syndrome (ALGS; OMIM #118450) is a highly variable, multi-systemic, autosomal dominant disorder, caused by mutations in the Jagged Canonical Notch Ligand 1 (JAG1) gene (20p12.2) or in the Neurogenic locus notch homolog protein 2 (NOTCH2) gene (1p13).1 It primarily affects the liver, heart, eyes, face, kidney, skin, vertebrae, and skeleton.1,2 The JAG1 gene has 26 exons and about 90% of the ALGS cases result from pathogenic variants in the JAG1 and around 7% of cases have deletions in chromosome 20 that include this gene.1,3 Latest reports reveal that the spectrum of mutations includes 75% protein-truncating mutations and the rest 25% are non-protein-truncating mutations. Few cases (<1%) have also been reported with pathogenic variants in a second gene called NOTCH 2 gene.1,3,4 Various studies have elucidated that ALGS clinical phenotype is caused by different pathogenic mutations in JAG1 and NOTCH2 genes suggesting the haploinsufficiency of these two genes as the primary mechanism for disease pathobiology rather than a dominant negative mechanism.1,2 Here we present a case report of two protein-truncating JAG1 mutations detected in two unrelated cases of South Indian origin.

Mucopolysaccharidoses (MPS) are a group of rare inborn errors of metabolism caused by defective lysosomal enzymes which prevent cells from degrading and recycling certain carbohydrates and fats, resulting in the storage of glycosaminoglycans in cells throughout the body. This leads to multisystem abnormalities involving bone, connective tissues, brain, blood, spinal cord, skin, and other tissues. In humans, seven distinct types and many subgroups of MPS have been classified, and each is linked to deficiencies of the specific enzymes. Very recently, two studies1,2 have suggested defects in ARSK may lead to a new MPS subtype, MPS X, in humans. Here we report a 13-year-old cognitively intact boy diagnosed with Perthes disease and pectus carinatum referred for possible skeletal dysplasia. Exome sequencing analysis of his peripheral blood sample revealed a novel homozygous missense variant, c.1067C>A (p.S356Y) in the ARSK gene, functionally proven to result in ARSK deficiency, evidenced by failure to remove the 2-O-sulfate group from 2-sulfoglucuronate. Urine glycosaminoglycan (GAG) examination with a more sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method confirmed a significant increase in dermatan sulfate, suggesting malfunction of glycosaminoglycan metabolism. Skeletal abnormalities of vertical striae of distal femoral bones and bilateral Perthes were consistent with those observed in previous cases.1,2 Based upon the collective results of functional studies, urine GAG analysis, and skeletal findings, the novel homozygous missense germline variant in ARSK (c.1067C>A, p.S356Y) was determined to cause an MPS disorder due to ARSK deficiency. This novel ARSK pathogenic variant will be useful in diagnosis/prognosis and highlights the important and unique roles of ARSK in the degradation of sulfated glycosaminoglycans and maintenance of normal lysosomal functions in humans.

With the rapid advances in stem cell research and potential cell-based therapies, there is an urgent need to develop safe and reliable cell transport strategies. Except for autologous stem cell-based therapies, allogeneic stem cell therapies and ex vivo genetically engineered cell therapies would require safe, efficient, and reliable cell preservation and transport methods.1 Conventional cell transport methods include shipping live cells in medium-filled culture flasks at room temperature or ambient/hypothermic conditions (<35 °C) within several days, or expeditiously transporting cryogenically preserved cell vials in dry ice or liquid nitrogen,2 as it is commonly believed that hypothermic preservation benefits cell survival by reducing cellular metabolic rate and oxygen demand.3 While the former approach is convenient with variable outcomes, the latter is expensive, environmentally unfriendly, and technically challenging for long-distance transport. Here, using the mesenchymal stem cell (MSC) iMEFs as a model cell line,4 we developed a simplified, inexpensive, and noncryogenic method to transport cells, especially. By optimizing several crucial parameters including storage temperature, cell density, fetal bovine serum (FBS) concentration, and pH stability, we found that the cell viability remained 16%–18% when 2–10 × 105 cells were stored in 1 mL of 2% FBS DMEM in a 1.5 mL Eppendorf tube at 4 °C–16 °C for up to 10 days. Furthermore, we demonstrated that the MSCs recovered from the above conditions maintained normal morphology, expressed stem cell markers, and retained osteogenic and adipogenic differentiation potential upon BMP9 stimulation in vitro and in vivo. Thus, our study identified an inexpensive, noncryogenic and reliable strategy for storage and transport of MSCs, potentially most mammalian cells.

ADAM8 has been identified as the fibronectin-cleaving enzyme in human degenerative intervertebral disc (IVD) tissues.1 Increase of the active form of ADAM8 and its cleavage product, fibronectin fragment, correlated with an increased degree of IVD degeneration.1 Furthermore, fibronectin fragments have been shown to accelerate the progression of IVD degeneration.2 These findings suggest that ADAM8 may play a role in degenerative disc disease, a clinical problem with tremendous socioeconomic burdens in the United States.3

Alcohol consumption contributes to global mortality and cancer development. Acetaldehyde (ACE), the oxidized metabolite of alcohol, is highly reactive towards DNA, resulting in DNA adducts. ACE can be detoxified to acetate by acetaldehyde dehydrogenase type 2 (ALDH2). ALDH2 deficiency can lead to ACE accumulation and DNA damage.1 Thus, ALDH2 deficiency is considered pro-oncogenic.2 Interestingly, there are more than 540 million people carrying a polymorphism of the enzyme, ALDH2.2∗ a dominant-negative variant that has substantially reduced enzymatic activity. This suggests that ALDH2 deficiency is well tolerated in humans. Surprisingly, a recent epidemiological report shows that the risk of homozygotes of ALDH2.2∗ carriers for IARC alcohol-related cancer and lung cancer is significantly reduced, rather than increased, in men.3 This is contradictory and perplexing since ACE or reactive oxidative species (ROS) is pro-oncogenic. However, there is no explanation.

The CD9 gene, also known as the Tspan29 gene, codes for a protein called CD9, which is a member of the tetraspanin family of transmembrane proteins.1 The CD9 protein is involved in various cellular processes, including cell proliferation, differentiation, adhesion, and migration.1,2 CD9 has also been found to play a role in the regulation of stem cell proliferation and differentiation.1 Overall, the CD9 gene and its encoded protein play important roles in cellular processes related to proliferation, and further research may uncover new insights into its functions and potential therapeutic applications.1,2 CD9 is involved in a variety of cellular processes that occur at the plasma membrane, including cell adhesion, migration, and signaling.1 It has been shown to interact with other proteins in the plasma membrane, such as integrins, and to modulate their functions.1 CD9 also plays a role in the formation of tetraspanin-enriched microdomains or tetraspanin webs, which are specialized regions of the plasma membrane that are involved in signaling and membrane organization.1 In addition to its role in the plasma membrane of cells, CD9 has also been found in extracellular vesicles, including exosomes, which are released from cells and can play a role in intercellular communication.3 CD9 in exosomes has been shown to play a role in promoting cell adhesion, migration, and invasion in cancer cells.2,3 We overexpressed CD9 in induced pluripotent stem cells and observed high proliferation, enhanced pluripotency, and growth of stem cells. CD9 overexpression has been found to promote cell proliferation, migration, and invasion, as well as resistance to apoptosis.1,4 The effects of CD9 overexpression can vary depending on the specific cell type, the level and duration of overexpression, and other factors.2,5 Further research is needed to fully understand the mechanisms underlying the effects of CD9 overexpression and its potential therapeutic applications.

Aicardi-Goutières syndrome (AGS) is a systemic inflammatory disorder caused by mutations in any one of the nine different genes, whose deficiency provokes a type I (interferon) IFN response probably central to pathogenesis.1 ADAR1, one of the genes mutated in AGS (AGS6), encodes for an enzyme that belongs to the ADAR family (ADAR1, ADAR2, and ADAR3) that catalyzes the conversion of adenosine to inosine within double-stranded RNAs (dsRNAs) (RNA editing A-to-I).2,3 Two main isoforms of ADAR1 are expressed in mammals: the full-length p150 that is interferon-inducible and the constitutively expressed shorter isoform p110.2,3

The estrogen signaling system is a crucial regulator of metabolic and physiological processes. However, abnormal activation of estrogen signaling may play a role in breast cancer initiation and progression. Crucial to this pathway is the interaction between estrogen receptor alpha (ERα) and various co-transcription activators.1 Although numerous studies have investigated ER coregulators, the protein–protein interaction networks of ERα are not fully understood. Recent research has shown that high chromodomain helicase DNA-binding 4 (CHD4) expression is linked to poor prognosis in various cancers.2,3 In this study, we demonstrated that both CHD4 and ERα contribute to breast cancer progression while providing evidence of the regulatory processes and functional interplay between these two proteins.

Congenital melanocytic nevi (CMNs) are skin lesions characterized by benign melanocytic proliferations and present at birth or shortly thereafter. Large and giant CMNs, with a projected adult size ≥ 20 cm and 40 cm in diameter respectively, are more likely to develop into malignant melanoma. In most cases, melanoma arising from congenital melanocytic nevus (CMN) is particularly aggressive.1 Meanwhile, there are no standard recommended guidelines specific to the treatment of CMN. Due to the extensive tumor size, complete removal of the plague is difficult. Less invasive treatment options are urgently needed. It is estimated that about 80% of CMNs and 95% of giant CMNs carry NRAS-activating mutations.2 However, targeting mutant NRAS is still not feasible. Since NRAS mutations can constitutively activate the mitogen-activated protein kinase (MAPK) pathway and fuel melanocytes proliferation and transformation, targeting MAPK kinase (MEK), the key downstream of the MAPK pathway, becomes a feasible treatment strategy for CMN. Indeed, there have been sporadic reports showing that trametinib, a MEK inhibitor, was effective in patients with mutant NRAS-driven central nervous system melanoma and giant CMNs.2,3 However, whether CMN patient is responsive to MEK inhibitor is still unknown. Here, we report a 2-year-old CMN patient carrying an NRAS-activating mutation with an objective response to trametinib.

Co-altered pathways refer to the phenomenon where multiple biological pathways exhibit aberrant changes simultaneously within the same tumor sample. This phenomenon can facilitate a better understanding of the mechanism and evolution of tumors and serve as a biological marker for diagnosing, classifying, and treating tumors.1 However, the nature of alteration occurrence and the impact on pancreatic adenocarcinoma (PAAD) remain elusive. The SELECT algorithm was originally designed to systematically assess the evolutionary dependencies and their impact between altered genes in cancer for anticipating drug resistance and proposing alternative strategies. Here, to better characterize the etiology of PAAD and develop an improved risk assessment strategy,2 by utilizing SELECT, we identified a co-altered pathway subgroup of PAAD that demonstrated an elevated risk for unfavorable prognosis, a propensity for liver metastasis, and an immunologically cold microenvironment.

Locoregionally advanced laryngeal and hypopharyngeal cancers (LA-LHCs) are traditionally treated with surgery followed by postoperative radiotherapy, which impairs speech and swallowing functions and reduces the quality of life.1,2 The use of induction chemotherapy (IC) as a larynx-preserving approach for LA-LHCs has been verified and refined.3 However, the short-term tumor response to IC varies, non-responders usually show poor survival and little benefit.4 Therefore, it is crucial to identify IC responders and avoid ineffective treatment. We sought to develop and independently validate a gene-expression signature to predict the efficacy of IC in LA-LHC patients, which would help clinicians select patients who would benefit from IC and provide individual advice for precision treatment, paving the way toward biomarker-driven treatment strategies (Fig. 1).

Endometriosis (EM) is a common disease that affects approximately 10%–15% of women of childbearing age. The pathogenesis of EM is unclear, but studies have shown a strong association between EM and inflammation, as well as oxidative stress.1 Pyroptosis is also called inflammatory cell death. When pyroptosis occurs, it activates a strong inflammatory response. Pyroptosis is associated with oxidative stress, and ROS act as intermediate triggers to activate pyroptosis, which can exacerbate the subsequent inflammatory cascade.2 However, it is unknown whether pyroptosis is regulated by oxidative stress during EM. Curcumin (CUR) is one of the world's best-selling natural food colorants and has a variety of pharmacological activities, including anti-inflammatory and antioxidant activities, and the pharmacological effects of CUR are associated with the mechanisms of pyroptosis and EM.3,4 In the present study, we showed that CUR ameliorated the inflammatory environment of EM by modulating oxidative stress and inhibiting GSDMD-mediated pyroptosis involving the NLRP3 inflammasome. These results further confirm the inflammation and oxidative stress theory of EM and provide new drug options for EM treatment.

The important role of immunogenic cell death (ICD) in many tumors is increasingly being discovered. However, its mechanisms and potential as a biomarker and therapeutic target in glioblastoma (GBM) have not been well studied. We obtained GBM samples from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, as well as the immunotherapy cohort from the IMvigor210 study. We used unsupervised clustering to obtain two ICD-related clusters, corresponding to the ICD-low and ICD-high subtypes respectively, and the tumor immune microenvironment and prognosis of the two subtypes were significantly different. Subsequently, based on the differentially expressed genes of the two subtypes, we constructed an ICD-related prognostic risk score model by LASSO-Cox regression analysis and constructed a nomogram chart, which can accurately predict the survival prognosis of GBM patients. Further analysis showed that risk score was an independent prognostic factor for GBM patients, and risk score was also confirmed to be correlated with mutation information, immune cells, immune-related pathways, and immunotherapy response. Our results suggest that ICD plays a role in the formation of GBM's tumor microenvironment, influencing the development of tumors, and highlighting the potential of ICD-related genes as prognostic biomarkers, therapeutic targets, and immune response indicators for GBM (Fig. 1 and Table S1).

CircRNAs, a novel type of endogenous non-coding RNAs (ncRNAs), are typically produced by back-splicing from exons of protein-coding genes, which are characterized by a covalently closed structure with neither 5′ to 3′ polarity nor a poly(A) tail.1 On the one hand, circRNAs are involved in the regulation of a variety of important biological processes, such as apoptosis, proliferation, migration, and inflammatory responses.1 On the other hand, the relationship between circRNAs and several fibrotic diseases has been reported.2 However, the functions of circRNAs in peritoneal fibrosis (PF) are still unknown. Herein, we first reported the circRNA expression profile in the high glucose peritoneal dialysis fluid (HG-PDF)-induced PF mouse model, and the differentially expressed circRNAs between the PDF group and Sham group. The Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and the construction of circRNA–miRNA–mRNA network provided an overview of the role of circRNAs in the development of PF. In addition, novel_circ_0007527 was up-regulated in the in vitro model of injured peritoneal mesothelial cells. Knockdown of novel_circ_0007527 inhibited peritoneal mesothelial epithelial–mesenchymal transition (EMT), proliferation, migration, and apoptosis. Therefore, our study provides novel avenues for PF research from the view of circRNAs.

Metabolic syndrome (MetS) is a complex disorder characterized by the coexistence of phenotypes such as obesity, hypertension, hyperglycemia, high triglyceride level, and low level of high-density lipoprotein cholesterol. Inflammation majorly driven by oxidative stress has an overarching role in obesity and IR-mediated mechanisms leading to MetS. Besides these factors, the molecular linkages between the MetS components and prognostic biomarkers for the prediction of the progression of one component to the others are still elusive. MetS is linked to several morbidities such as type-2 diabetes (T2D), non-alcoholic fatty liver disease, and cardiovascular diseases. Recently, there has been a surge in evidence linking ferroptosis, through iron overload and lipid peroxidation-driven cell death, and diseases such as cardiovascular diseases and T2D. The role of ferroptosis in liver diseases is well characterized as hepatocytes play a major role in iron transport and metabolism. Collectively, the above findings indicate the likelihood of ferroptosis contributing to MetS pathology. Here we have systematically collated and analyzed the high throughput data on MetS generated using various platforms such as GWAS, RNA-seq, and microarrays using a non-quantitative meta-analysis approach to evaluate and compare the expression of molecular mediators of ferroptosis in MetS and its co-morbidities such as T2D and hypercholesterolemia (Fig. 1).

Colorectal cancer (CRC) is one of the most common cancers around the world, and it is one of the leading causes of cancer-related death.1 Although anti-EGFR therapy and immune checkpoint inhibitor (ICI) therapy are becoming more and more important for colorectal therapy, however, clinical outcomes of current treatments for metastatic CRC, especially with ICIs, have been shown to be affected by the status of KRAS. Therefore, KRAS mutation status detection has become a very important diagnostic factor for managing metastatic CRC patients. There have also been a lot of immunotherapy explorations in CRC, such as clinical trials of pembrolizumab and nivolumab. The clinical trial Keynote 177 is a groundbreaking research in CRC, which evaluated the efficacy of programmed death 1 blockade as first-line therapy for MSI-H-dMMR advanced or metastatic CRC. However, the results of subgroups revealed that immunotherapy did not benefit more than chemotherapy in patients with KRAS mutation.2 While the mechanism behind these clinical results keeps unclear, herein, we comprehensively analyzed the genetic and immunologic characteristics of CRC with KRAS mutation, and try to explore the mechanisms and potential predictive biomarkers, especially from the prospect of tumor immune microenvironment (TIME).

Uncoupling protein 1 (UCP1, also known as thermogenin or SLC25A7) plays an important role in the uncoupling of oxidative phosphorylation and adaptive non-shivering thermogenesis (NST). The genomic location for UCP1 is chromosome 4 q31.1:140,555,770–140,568,961 (GRCh38/hg38) and its size is 13,192 bases split into 6 exons. In dbSNP, 3650 short genetic variations of human UCP1 are documented. In this study, UCP1 serves as an example to construct polymorphism-trait networks and enable a functional classification.

Interleukin-6 (IL-6) is a common pluripotent cytokine that is highly expressed in the tumor microenvironment. The IL-6/JAK/STAT3 signaling directly promotes tumor progression, severely hampering antitumor immunity. Macrophages, the richest innate immune cells within the tumor microenvironment, manipulate tumor progression via phenotypic plasticity. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are two critical growth factors regulating macrophage differentiation and function. They play different roles during tumor development; while GM-CSF links with enhanced antitumor immunity, M-CSF is associated with M2-like phenotypes of tumor-associated macrophages. Nevertheless, the signaling response of differentially differentiated macrophages to IL-6 has not yet been elucidated. Here, we explored IL-6 downstream signaling events in two distinct macrophage populations (M1-like proinflammatory GM-CSF primed and M2-like immunosuppressive M-CSF primed bone marrow-derived macrophages, GM-BMDMs vs. M-BMDMs). We found that IL-6 preferentially induces JAK2/TYK2/STAT3 activation in M-BMDMs due to their higher glycoprotein 130 (gp130) expression. In vivo, STAT3 phosphorylation is largely present in macrophage populations within the tumor microenvironment. Importantly, the gp130 inhibitor could effectively reverse the tumor-promoting effects of M-BMDMs via IL-6/STAT3 signaling blockage, pointing to its potential therapeutic usage for tumor treatment.

Opioid abuse can suppress the lymphatic system function, and produce severe immunosuppression that poses a significant risk of opportunistic infections such as methicillin-resistant Staphylococcus aureus (MRSA) pneumonia.1,2 Gypenosides (Gps) are the most important immunomodulator components in the Chinese herbal medicine Gynostemma pentaphyllum.3 However, the immunomodulatory mechanism and effect of Gps on morphine-induced immunosuppression are still unknown. We aimed to investigate the pharmacological effects of Gps in morphine-induced immunosuppressive mice and the underlying mechanism involved.

The ovary is a vital female reproductive organ that functions to produce oocyte gametes and cyclically expressed sex hormones to maintain reproductive capacity and hormone homeostasis. Ovarian aging, characterized by declines in follicle quantity and oocyte quality, leads to premature ovarian failure, premature ovarian insufficiency, or diminished ovarian reserve, thus contributing to female infertility. Distinct gene-expression signatures from RNA transcriptional level and post-transcriptional regulation are relative to oocyte quality and reproductive age.1 Mouse follicular transcriptome-wide N6-methyladenosine (m6A) landscape revealed that dynamic m6A modification exists in the process of maternal-to-zygotic transition, which depended on the regulation by the m6A methyltransferase complex.2 m6A writing mediated by maternal methyltransferase-like 3 (METTL3) is a key role in the establishment of m6A on oogenesis and pre-implantation embryo development.2 Methyltransferase-like 14 (METTL14) serves as the core subunits to catalyze effective methyl group transfer and is an important role in promoting the aging-associated phenotype and reprogramming.3 However, the regulatory mechanisms from m6A association complements during the process of ovarian aging remain incompletely explored.

Pseudohypertrophic muscular dystrophy is a lethal X-linked recessive neuromuscular disorder caused by mutations in the dystrophin gene. This gene encodes a cytoskeletal protein that is extensively expressed in muscle cells and that enables the strength, stability, and functionality of myofibers. Muscular dystrophy can be grouped into two different categories based on the mutational rate and clinical severity, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). DMD is the most common and the more severe type of dystrophy. DMD patients usually become wheelchair-bound by the age of 12 years and die in their late teens to early twenties.1 In contrast, BMD is relatively less severe and the patients can potentially have a longer life expectancy.

Melanoma is a lethal skin malignancy and the fifth most diagnosed cancer in the United States.1 Currently, for unresectable melanoma, the recommended treatment options include checkpoint inhibitor immunotherapy targeting programmed cell death 1 (PD-1), and inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway.2 However, the response rate may vary among the patients, and therefore demanding the development of novel treatment strategies. Tumor suppressor TP53 has been suggested as one of the critical regulators mediating the aggressiveness and progression of melanoma. Over 80% of melanoma patients harbor the wild type (WT) yet malfunctional p53, which leads to the investigation that focused on restoring the function of p53 in melanoma as an alternative treatment strategy.3 The degradation of p53 is catalyzed by mouse double minute 2 (MDM2), a well-known E3 ubiquitin ligase. Based on a previously reported MDM2 inhibitor, MX25, which has an iodide counter ion and is highly susceptible to oxidation in the air, we designed a new MX25 analog JW-1-283 using a stable ethyl sulfate group as the counter ion. In the current research, we investigated the anti-melanoma effect of JW-1-283 and leverages it as a novel p53-activating reagent.

Bone regeneration is a multifaceted, abstract, and well-coordinated physiological progression of bone formation that participates in continuous regeneration and remodeling throughout life. However, when it comes to complex clinical situations requiring extensive bone regeneration, such as massive bone defects caused by injuries, infection, or tumor removal, traditional methods do not often yield good treatment strategies or protocols due to their limitations.1 Stem cells, which have been shown to differentiate into diverse lines, have great potential to treat many diseases.2 The stem cells provide an excellent opportunity to study local strategies for bone healing and even systematic enhancement of bone repair, thereby overcoming the limitations of current methods. PDZ and LIM domain 5 (PDLIM5) is regarded as a cytoskeleton-related protein that is intimately connected to the dynamic alterations of microfilaments and can mediate signal transmissions between the cell nucleus and the cytoskeleton. PDLIM5 is also defined as a mechanosensitive protein that exhibits tension-dependent nuclear translocation in cells, displaying a mechanoconductive relationship with Yes-associated protein (YAP).3 Therefore, it is useful to further understand PDLIM5's molecular mechanism in osteogenic differentiation to study how it transfers external mechanical stimulation to the nuclear skeleton through the cytoskeleton and controls osteo-genes.

Aerobic exercise training alters gene expression in skeletal muscle, and miRNAs significantly contribute to motion response. However, the molecular mechanisms by which miRNAs regulate the response to exercise training are not well understood. Here, we found that the abundance of miR-378a-3p in skeletal muscle significantly decreased after exercise training. miR-378a-3p knockout mice showed increased insulin sensitivity, insulin-mediated glucose uptake, and an oxidative phenotype, recapitulating the role of miR-378a-3p in exercise-induced adaptations of skeletal muscle. Mechanistically, miR-378a-3p modulates insulin-mediated glucose uptake through the IGF1/IGF1R-AKT-GLUT4 axis by targeting Igf1r and Igf1. Additionally, loss of miR-378a-3p promotes the tricarboxylic acid (TCA) cycle by promoting the process of oxaloacetic acid synthesis by targeting Car5b. Moreover, deletion of miR-378a-3p alleviates obesity and improves glucose metabolism in mice fed a high-fat diet, suggesting its potential as a therapeutic target for metabolic diseases. Overall, our findings highlight the crucial role of miR-378a-3p in regulating insulin-mediated glucose uptake and TCA cycling in skeletal muscle, offering promising therapeutic implications for metabolic diseases.

The multiple PDZ domain crumbs cell polarity complex component gene (MPDZ; MIM: 603785), is highly expressed in the brain across the whole lifespan. It encodes the multiple PDZ domain protein, which is a member of the NMDAR signaling complex that may play a role in the control of AMPAR potentiation and synaptic plasticity in excitatory synapses.1 Previously, MPDZ variants have been demonstrated to be associated with autosomal recessive congenital hydrocephalus-2 (HYC2; MIM: 615219) which is commonly complicated by brain abnormalities and developmental delay. Seizures were reported in only one case. The association between MPDZ and epilepsy requires clarification.

Progressive osseous heteroplasia (POH) is an ultra-rare autosomal dominant disabling disorder characterized by heterotopic ossification (HO). It is caused by heterozygous inactivating mutations in the GNAS (guanine nucleotide-binding protein alpha-stimulating activity polypeptide) gene. However, the molecular mechanisms underlying HO remain poorly understood. As a treatment for POH is not yet available, the identification of the mechanisms driving POH in affected tissues using gene expression may be of great help to underestand the molecular basis of POH and develop new therapeutic approaches.

Approximately 20%–25% of adults encounter metabolic syndrome (MetS) worldwide, and MetS is a risk factor for cognitive decline (CD) development. Patients with MetS have an 11.48-fold increased incidence of CD compared with those without MetS.1 Ataxia-telangiectasia mutated (ATM) gene encodes ATM kinase, which belongs to the phosphatidylinositol 3-hydroxy kinase family. Reduced ATM gene expression creates an inhibitory hippocampal function, excitatory/inhibitory imbalance, and finally CD.2 Based on the China Hainan Centenarian Cohort Study (CHCCS) performed in 18 cities and counties of Hainan, we showed that the frequency of CC genotype in single nucleotide polymorphism (SNP) rs189037 was significantly higher and that of TT genotype was significantly lower in centenarians with MetS than in those without MetS. Compared with CC and CT genotypes, TT genotype was negatively and significantly associated with MetS but not CD. This study demonstrated that mutant SNP rs189037 in ATM gene had a significantly negative association with MetS but not CD in Chinese centenarians.

Androgen receptor (AR) is a major transcription factor that plays a role in inflammatory response including interleukin-6 (IL6) signaling.1 While AR regulation through paracrine loop signaling in prostate tissue is well-studied, its impact through an IL6 autocrine loop in the lung has not been well-studied despite the organ's response to respiratory viral infection. Chemical inhibition and RNA knockdown of AR identified a bZIP transcription factor MAF to be a common target of inflammation using these perturbations in lung cells. We hypothesized through a predictive in silico network modeling that MAF is a common mediator between androgen signaling and inflammatory response in lung cells exposed to AR antagonists and viral (SARS-Cov-2) infection.

Metatropic dysplasia (MD, MIM 156530) is a rare congenital bone dysplasia primarily characterized by severe platyspondyly with long and wide vertebral bodies and dumbbell deformity of the tubular bones. MD can be caused by heterozygous mutations in the gene encoding transient receptor potential vanilloid family member 4 (TRPV4). We identified a novel de novo mutation, c.2353 T>C, in the TRPV4 gene, in a Chinese family with mild MD. Expression of mutant TRPV4 in HEK293 cells resulted in higher basal intracellular Ca2+ concentrations and endoplasmic reticulum redistribution. In addition, mutant TRPV4 inhibited the chondrogenic differentiation of ATDC5 cells. Overall, we concluded that the novel mutation c.2353 T>C in the TRPV4 gene was the causative genetic lesion in this MD patient, whilst its pathogenicity might be partially attributed to the inhibition of chondrogenic differentiation.

Primary Sjögren's syndrome (pSS) is one of the most widespread autoimmune diseases with unknown origin, characterized by a lymphocytic infiltrate of the exocrine glands and the production of anti-SSA/Ro and anti-SSB/La antibodies that cause dysfunction and destruction mainly of salivary and lachrymal glands, leading to dry eyes and dry mouth. In the absence of a standardized evidence-based screening tool to decide which patients with dry eye must be referred for study of this pathology, there is a tendency to have a continuous underdiagnosis of the disease, causing the calculation of its prevalence to be inaccurate.1 To improve our understanding of the underlying molecular nature, we analyzed public microarray-based gene expression profiles of salivary glands (GSE23117) and saliva (GSE7451) from primary Sjögren's syndrome (pSS) patients and controls. Unlike the two microarrays published before, we showed a specific common set of genes and an extensive study of biological pathways and networks showing a potential detonating factor. We included a machine learning model to distinguish pSS patients from controls, opening a possible means of detecting biomarkers to diagnose, monitor the response to treatment, and predict the prognosis of pSS.

Esophageal squamous cell cancer (ESCC) is one of the malignant tumors with high morbidity and mortality all over the world.1 In recent years, combined chemotherapy has gradually been the effective treatment method for ESCC patients. Therefore, it is imperative to explore potential therapeutic targets for the treatment of ESCC. We previously reported a high-frequency amplification of pyrimidine metabolic pathway-related genes in ESCC tissues,2 and ribonucleotide reductase subunit M1 (RRM1) was one of many abnormal genes. RRM1 is one of the important subunits of ribonucleoside reductase (RR) and plays a key role in cell DNA replication as a binding site of nucleotides to regulate substrate specificity and RR activity. RRM1 is expressed in almost all tumor cells, but its expression levels and functions are differently affected by tissue origin and cell location. The expression of RRM1 in lung cancer tissues was generally lower than that in adjacent tissues, while an opposite trend was observed in breast cancer. Reports about RRM1 in ESCC are less, and the mechanism(s) of carcinogenesis is still poorly understood. The present study aimed to understand the role of RRM1 on the malignant proliferation process, and further clarify the molecular mechanism in ESCC development, which would be helpful in anti-cancer therapy of ESCC patients.

Esophageal cancer is one of the leading causes of cancer death in the world, with approximately half of the new cases occurring in China every year.1 Esophageal squamous cell carcinoma (ESCC) is the main subtype, accounting for more than 90%, and the five-year survival rate is less than 10%. Using large-scale genome analysis, many driver mutations and key pathways associated with ESCC have been identified. However, these genomic signatures have not improved the clinical management of ESCC patients, or established effective targeted therapy.2 Esophageal cancer still lacks representative molecular markers.

Post-translational modifications (PTMs) play a critical role in bone remodeling, with phosphorylation and acetylation being particularly well characterized. Recently, succinylation, a relatively uncommon PTM on lysine, has received considerable research attention for its influence on several physiological and pathological processes and conditions.1 Several substrates involved in mitochondrial pathways have been validated as substrates for the desuccinylase sirtuin 5 (Sirt5), a key regulator of succinylation.2 Bone is one of the most metabolically active organs, but the role of succinylation during bone remodeling is not well characterized.

Cancer of unknown primary (CUP) is a rare disease characterized by metastases in which the primary tumor is of unknown origin. The cerebrospinal fluid (CSF) tumor microenvironment of CUP is still unknown. A Chinese male was diagnosed with leptomeningeal metastases from CUP (CUP-LM) based on the following medical examination results: partial leptomeningeal enhancement by brain magnetic resonance imaging, few malignant cells of diverse morphology in CSF, and no abnormalities or lymphadenopathy by systemic examination. The CSF tumor microenvironment was analyzed by single-cell RNA sequencing (10× genomics). A total of 3346 cells of high quality were enrolled for analysis and classified into eight major cell types. The CSF tumor microenvironment of the CUP-LM case showed CD8+ T cells in a dysfunctional state, an increased proportion of regulatory T cells (Treg) and LAMP3-positive dendritic cells, which helped shape an immunosuppressive landscape. In addition, intensive communications between CD4_Treg and other cell subtypes were identified from aspects of inhibitory, costimulatory, or chemokine communications. The tumor cells enhanced the immunosuppressive tumor microenvironment by the interaction of co-inhibitory checkpoints with the tumor-infiltrating immune cells.

Melatonin is an endogenous monoamine hormone secreted by the pineal gland. Melatonergic signaling has been shown to play a role in circadian rhythm regulation, lipid and glucose metabolism, and obesity, and it has anti-inflammatory and antioxidant properties. The melatonin receptor 1B gene (MTNR1B) is expressed in, among other tissues, the brain and pancreatic beta cells, and risk variants for T2D have been reported as impairing early insulin secretion and increasing fasting glucose levels.1 Variants in the MTNR1B gene also have been reported in patients with depression (MDD).2