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。

过刊浏览

Epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer is a dynamic entity, with tumor progression and resistance to tyrosine kinase inhibitors (TKIs) stemming from the accumulation of mutations over time and across different disease sites, leading to temporal and spatial heterogeneity.1 Based on the presence of EGFR T790M and the allelic background of C797S-T790M, four subgroups of patients after three-generation EGFR-TKI resistance can be distinguished: EGFR T790M-C797S in cis subtype; EGFR T790M-C797S in trans subtype; EGFR T790M-C797S in trans and cis subtype; and wild-type EGFR codon T790M but carrying the C797S mutation, hereinafter referred to as C797S-only.2 While treatment modalities have emerged for the different mutant subtypes, a recent study has found that the prognosis for the EGFR T790M-C797S in trans and cis subtype and the C797S-only subtype remains poor.2 This may be due to dynamic changes in EGFR clones under therapeutic stress. Here, we report data for the evolution of the EGFR mutation in a patient with non-small cell lung cancer during disease progression under the pressure of EGFR-TKI therapy. In the patient's latest genetic test, we identified the coexistence of five different EGFR mutations, including EGFR L858R, EGFR T790M-C797S both in cis and in trans and EGFR L718Q. Then she was treated with a triplet therapy of EGFR-TKIs, and stabled for three months.

Smith-Kingsmore syndrome (SKS) is a very rare dominantly inherited disorder caused by a gain-of-function mutation in MTOR (mechanistic target of rapamycin).1,2 It is typically characterized by megalencephaly, developmental and intellectual delay, and distinctive facial traits. Attenuated SKS-like phenotypes from a somatic gain-of-function mutation in MTOR have also been reported.3,4 In most of these milder cases, mosaicism translated into focal brain cortical dysplasia, and in six cases, into a somewhat wider presentation such as ventriculomegaly, patchy hypomelanosis and a few additional SKS-like features (in all six cases), unilateral megalencephaly (in three), and hemihypertrophy (in one).

For prognosis and therapeutic response, colorectal cancer (CRC) patients are highly variable across stages, correlated to high inter-tumor heterogeneity at the molecular level.1 Therefore, molecular subtyping needs to be determined for stratifying patients into distinct prognostic subgroups according to tumor biology.2 Metabolic reprogramming is an important cancer hallmark and confers a few cancer phenotypes.3 Metabolic landscape, comprising metabolites, proteins, and their interactions remains high variability across pan-cancer or even the same cancer type with distinct conditions.4,5 Thus, comprehending the transcriptional changes of metabolite-interacting proteins (MIPs) may provide valuable insights into promising therapeutic targets. In the present study, CRC patients were categorized into two subtypes, namely C1 and C2 based on prognostic MIPs, and each subtype owned a distinct clinical outcome. Meanwhile, an MIP-relevant risk score was generated and could accurately predict survival outcomes and personalized therapy for CRC based on bioinformatics mining. Additionally, a MIP-relevant gene, insulin-like growth factor-binding protein 3 (IGFBP3) was overexpressed in CRC tissues, and deficiency of IGFBP3 could facilitate the accumulation of intracellular reactive oxygen species and inhibit mitophagy in CRC cells. In summary, the current study proposed robust MIP-based molecular subtyping and relevant risk scores for guiding therapy selection and prognosis prediction of CRC patients, which might facilitate comprehension and clinical application for CRC metabolism heterogeneity.

Gene overlap serves as a common strategy employed by bacteria and viruses to expand their genomic capacity. Over the past two decades, advances in omics studies have unveiled a prevalence of overlapped genes in eukaryotes, including mammals. However, few are reported to participate in the regulation of the cardiovascular system. In this study, we introduce a novel protein-coding nested gene, named Aff3ir, which contributes to endothelial maintenance by promoting the differentiation of vascular stem/progenitor cells (SPCs) into endothelial cells (ECs).

Seed cells, scaffold materials, and growth factors constitute the three fundamental components of bone tissue engineering.1 In recent years, human adipose-derived stem cells (hASCs) have emerged as promising candidate cells owing to their several sources and strong differentiation ability.2 Therefore, studying the mechanisms underlying the osteogenesis of hASCs is crucial for further progress in bone tissue engineering. With the aid of bioinformatics, we conducted a comparative analysis of the differentially expressed genes between osteogenically induced and uninduced groups and identified a crucial gene, Eg5. Eg5, alternatively referred to as KIF11 or Eg5 kinesin motor protein, is a constituent of the kinesin motor protein family, exerting a substantial influence on the initial phases of cellular division through its regulation of spindle formation and functionality.3, 4, 5 Previous literature has suggested that Eg5 could generate the sliding force on the spindle pole microtubules, pushing the two extremes of the spindle away from each other and aiding in the accurate separation of chromosomes into daughter cells.5 Our team has long focused on the changes in the cytoskeletons in osteogenesis and found that microfilaments and microtubules are closely related to the osteogenesis of hASCs. Based on these findings, we hypothesized that Eg5, microtubules, and actin microfilaments might cooperate to regulate the osteogenesis of hASCs. Therefore, the present study focused on determining a potential regulatory association among Eg5, microtubules, and actin microfilaments and the direction of signal transduction across these elements. These findings will contribute novel perspectives and methodologies to inform future investigations in the field of bone tissue engineering.

CSF1R-microglial encephalopathy (CME) is a rare dementia with rapid development of cognitive impairment. The main clinical features of CME are progressive cognitive impairment, motor dysfunction, and neuropsychiatric symptoms.1 Pathological features of CME showed diffuse leukoencephalopathy and thin corpus callosum, and immunohistochemical staining showed axonal bulbous transformation with pigmentary glial cells, extensive axonal degeneration, and myelin loss. The clinical phenotypes of CME are complex and varied, including progressive cognitive decline, movement disorders, seizures, psychobehavioral abnormalities, and multiple complications. The initial clinical manifestations of the disease vary greatly and are non-specific, so it is easy to be missed or misdiagnosed as Alzheimer's disease, multiple sclerosis, or other leukoencephalopathy. The average age of onset is 8–72 years (mean: 42 years) and the prognosis is poor with a median survival of 2–30 years (mean: 6 years). Current treatments include microglia replacement and symptomatic treatments, with no specific treatments for now. The main reason for this is that CME is difficult to diagnose because of its unknown mechanism, often requiring highly expensive gene sequencing.2 Most CSF1R mutation models reported to date are all knockout models, which cannot well mimic the clinical phenotype.3 CSF1R haploinsufficiency model mice show olfactory dysfunction, myelin hyperplasia, and increased reverse transcriptase of cortical oligodendrocytes, which have not been described in clinical lines.4 There has been no effective model of CME, and extensive knockout will cause gene deletions resulting in lethal defects. In this article, we proved that the CSF1RP853T/+ model can well imitate CME. This article explores the mechanisms of CME in the CSF1RP853T/+ mouse model and finds that CME suffers from abnormal intercellular communication, mitochondrial malformations, and enlarged lysosomes, worsening inflammation in the brain, which in turn exacerbate mitochondrial damage and form a vicious circle of predominantly immuno-inflammatory senescence. All animal protocols were approved by Yangzhou University's Institutional Animal Care and Use Committee and Animal Ethics Committee (No. YXYLL-2022-71), China, in accordance with the NIH Guidelines for the Care and Use of Laboratory Animals.

Breast cancer, recognized as a foremost cause of mortality among women, is characterized by a complex immune microenvironment. Alternative splicing (AS) is a crucial process leading to diverse transcript variants. Studies have shown AS's role in T cell and B cell stimulation. For instance, Shalek et al performed single-cell RNA sequencing and showed that different AS patterns existed depending on the maturity and differentiation of dendritic cells, such as Cxcl10.1 AS of CD28 enhances the viability of activated T cells.2 However, the role of AS in breast cancer, particularly in relation to immune cell infiltration, remains underexplored.

Glioma is the most aggressive and incurable brain tumor.1 Anoikis is programed apoptosis in which cells are detached from the cellular matrix and suspended to death.2 It plays a critical role in cancer progression. Cancer cells overcome anoikis via various methods to continue their progression and metastasis. But the role of anoikis in gliomas remains elusive. By comprehensively studying the glioma patient's data in public databases, we built an anoikis-related genes risk nomogram for glioma and validate independently. We found the high-risk groups were enriched in the anoikis and immune-related pathways. Further analysis of high-risk score groups revealed that they had higher immune infiltration, lower IDH-mutations, higher tumor mutation burdens and higher tumor immune dysfunction and exclusion scores, indicating that there might not be successful for the high-risk score glioma patients in immunotherapy. In conclusion, we built a risk modal by applying the analysis of anoikis-related genes and immune signature genes, and this risk modal can predict glioma patients' clinical outcomes successfully and accurately.

Apolipoprotein L1 (ApoL1), coded by ApoL1 gene that is only expressed in humans, gorillas, and green monkeys, is largely synthesized by the liver and incorporated into high-density lipoprotein (HDL), playing beneficial roles in inflammation and Trypanosoma brucei infection.1 To date, except for the neutral allele of ApoL1 G0 which is a major form discovered in humans, two human ApoL1 alleles have been identified, including ApoL1 G1 and ApoL1 G2, which are highly associated with various human kidney diseases in the population-based studies.2 Over the past two decades, the relationship between ApoL1 risk alleles and atherosclerotic cardiovascular disease remains largely unexplored. Different transgenic murine models expressing human ApoL1 risk alleles have been constructed; however, they are widely used to investigate the impact of ApoL1 on kidney diseases but not atherosclerosis because wild-type mice with overnutrient intervention are still resistant to atherosclerosis.3 Recently, emerging evidence shows that Syrian golden hamsters lacking low-density lipoprotein receptor (LDLR−/−) replicate familial hypercholesterolemia, providing an ideal animal tool for studying human atherosclerosis.4

Obesity is one of the major risk factors of non-alcoholic fatty liver disease (NAFLD), however, the reliable diagnostic markers are not fully known. The purpose of this study is to clarify the shared pathophysiological diagnostic markers of obesity and NAFLD. We analyzed mRNA expression profiles of NAFLD and obesity from the GEO database using WGCNA to identify gene modules. Lasso regression and receiver operator characteristic curve helped construct predictive models. Key genes were examined for function via multiple analyses, including in vivo experiments and immune infiltration. BBOX1, SSTR1, MMP7, and LACC1 emerged as common predictors for obesity and NAFLD through animal experimentation and predictive model analysis. Dendritic cells and macrophages were significantly altered in obesity and NAFLD (Fig. S1). Obesity and NAFLD share a molecular mechanism with BBOX1, SSTR1, MMP7, and LACC1, which play crucial roles in disease development and can serve as common predictors (Fig. S2, 3). Further research on drug–gene interplay may lead to new treatments.

Facial infiltrating lipomatosis (FIL) is a congenital disorder caused by the hyperproliferation of adipose and skeletal tissue within the facial region. Infiltration of mature adipose tissue into adjacent structures is a hallmark pathologic finding. In addition to the aesthetic implications, patients may suffer from impaired facial function, including difficulty in swallowing and breathing, sleep disturbances, and visual field displacement. FIL is associated with phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) variants. PIK3CA variants were detected in over 85% of FIL cases, spanning numerous tissue types. Prior research has indicated that PIK3CA hotspot variants may result in a more severe phenotype. However, identical PIK3CA variants can lead to varying degrees of phenotypic severity. This highlights the need for further exploration into the potential contribution of other pathogenic factors. In this study, we reported the co-occurrence of PIK3CA and isocitrate dehydrogenase 1 (IDH1) variants in two patients with FIL and intracranial lesions for the first time. Our study expands the genetic landscape of FIL and provides a view that variants in genes other than PIK3CA may be involved in the pathogenesis of overgrowth disorders.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and the leading cause of cancer deaths worldwide.1 Despite immunotherapy, radiotherapy, and chemotherapy advances, treatment outcomes remain unsatisfactory.2 Thus, prognostic models that accurately predict patient prognosis and guide individualized treatment are desperately needed. SUMOylation, a reversible post-translational modification, is a crucial molecular regulatory mechanism that affects tumor progression.3 However, the role of sumoylation-related lncRNAs (SR-lncRNAs) in LUAD has not been explored. This study aimed to construct and validate an SR-lncRNAs signature for predicting LUAD prognosis, tumor immune microenvironment, and therapeutic sensitivity.

Drug addiction is a complex brain disease closely related to the expression and methylation of many genes. Differential genes can influence addiction, and some key differential genes may have a significant impact on the occurrence and development of addiction. Nowadays, data on addictive drugs is widely available. To our knowledge, there are very few databases on genes related to addictive drugs, and existing addiction related databases are not available.1,2 Therefore, it is necessary to analyze existing data on drug addiction, identify genes that play a crucial role in addiction, and establish a database to store and display these results. To meet this requirement, we analyzed and integrated the results of 56 datasets from 10 addictive drugs to develop DARG (Drug Addiction Related Gene Database) (https://darg-database.cn/). Through various search modules, corresponding analysis results can be obtained, including differential analysis results, protein–protein interaction (PPI) network analysis results, centrality analysis results, enrichment analysis results, gene–drug correlation analysis results, etc. Meanwhile, DARG provides online analysis functionality, allowing users to upload a gene list to obtain key genes within these genes. DARG will be a valuable resource for studying addiction related genes, providing great convenience for researchers and clinical doctors.

Epilepsy is a prevalent and serious neurological disorder affecting more than 65 million individuals worldwide. The etiology of epilepsy is multifaceted, with genetic factors implicated in 70%–80% of epilepsy cases, based on early twin or family-based studies. Despite over 1000 monogenic epilepsy-associated genes have been identified, the etiology for over 50% of epilepsy cases with suspected genetic risk remains undetermined in both clinical and research studies.1 UNC13A, a gene encoding the presynaptic protein Munc13-1, plays a crucial role in neurotransmitter release at synapses.2 Although UNC13A variants have been reported to be associated with various neurological disorders,3 their involvement in epilepsy remains uncertain.

Schneider Ronen，Shril Shirlee，Buerger Florian，Deutsch Konstantin，Yousef Kirollos，Frank Camille N.，Onuchic - Whitford Ana C.，Kitzler Thomas M.，Mao Youying，Klämb t Verena，Zahoor Muhammad Y.，Lemberg Katharina，Majmundar Amar J.，Mansour Bshara，Saida Ken，Seltzsam Steve，Kolvenbach Caroline M.，Merz Lea Maria，Mertens Nils D.，Hermle Tobias，Mann Nina，Pantel Dalia，Halawi Abdul A.，Bao Aaron，Schierbaum Luca，Schneider Sophia，Salmanullah Daanya，Ben - Dov Iddo Z.，Sagiv Itamar，Eid Loai A.，Awad Hazem Subhi H.，Al Saffar Muna，Soliman Neveen A.，Nabhan Marwa M.，Kari Jameela A.，El Desoky Sherif，Shalaby Mohamed A.，Ooda Said，Fathy Hanan M.，Mane Shrikant，Lifton Richard P.，Somers Michael J.G.，Hildebrandt Friedhelm

Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of pediatric end-stage renal disease. Monogenic causes have been detected in 11%–45% of pediatric SRNS using exome sequencing,1, 2, 3 leaving a large proportion of cases without a molecular diagnosis. Here, we report employing trio exome sequencing analysis to detect established and novel causes of SRNS in an international cohort of 320 unrelated families with pediatric SRNS. In 88/320 families (27.5%), exome sequencing revealed a pathogenic variant in a known monogenic SRNS gene. In 18 families (5.6%), we detected a causative variant in a phenocopy gene. In families without a molecular diagnosis, exome sequencing data was evaluated for variants in novel genes. In 18.1% (58/320) of families, we detected variants in a single novel candidate gene for SRNS. In non-consanguineous families, trio analysis increased the rate of novel candidate gene discovery from 15.9% in singlets to 28.8% in duos/trios by detection of deleterious compound heterozygous and de novo rare variants (Fig. 1).

The adipose tissue is a crucial energy reservoir that can undergo significant changes during aging, impacting the pathogenesis of metabolic disorders, including obesity.1 Obesity affects individuals of all ages, with different implications for each stage of life. It is thought to be a state of accelerated aging, prompting the introduction of the term "adipaging", for which obesity and aging share key biological hallmarks strictly related to a dysfunctional adipose tissue.2 Understanding the complex molecular relationships between obesity and aging is crucial for developing effective strategies to mitigate their impact.2 As transcriptional studies can allow the identification of novel gene expression patterns and identify putative genes and regulatory pathways that could contribute to the development of diseases related to obesity, we conducted a computational integration of available total RNA sequencing datasets in obesity-affected patients, to obtain insights into the transcriptional differences present in the subcutaneous adipose tissue of obesity-affected children and adults in a wide cohort.

Hepatocellular carcinoma (HCC) is one of the most common tumors with high prevalence and death rate, which lacks effective targeting and immunotherapy currently. Metabolic reprogramming, which provides an inherent advantage for tumor cells to compete for nutrition, plays important roles in the development and progression of cancers.1 Increasing studies indicated that metabolic reprogramming of tumors can remodel the microenvironment through different signaling pathways and thus promote the development of tumors.2,3 In addition, long non-coding RNAs (lncRNAs) represent a subgroup of noncoding RNAs and have been shown to play extensive regulatory functions in cancer, such as signaling and immune pathways. Besides, it has been widely clarified that lncRNAs play important roles in bridging metabolic reprogramming and immunology.4 However, knowledge regarding the lncRNAs perturbed by metabolic reprogramming in HCC is still lacking. Therefore, an in-depth understanding of the downstream lncRNA pathways of metabolic reprogramming is of great significance for identifying new therapeutic targets for HCC.

Hepatic steatosis is prevalent worldwide and is characterized as excessive lipid accumulation with/without inflammation and injury in the liver. Hepatic ischemia-reperfusion (HIR) injury commonly occurs in the process of hemorrhagic shock, liver surgery, and liver transplantation, and impairs liver function by inhibiting the electron transport chain in mitochondria during ischemia stage and producing large amount of reactive oxygen species (ROS) during reperfusion stage.1 Steatotic livers are more susceptible to HIR injury due to redundant lipid ROS and immune imbalance, which could induce dysregulation of autophagy.2 Therefore, it is of great importance to explore viable strategies for the protection of steatotic livers from HIR injury. Human amniotic epithelial cells (hAECs), which are regarded as a promising cell type for cell-based therapies due to low immunogenicity and tumorigenicity, stem-cell-like plasticity, and paracrine properties, have been discovered to act in anti-inflammation and function repair of multiple tissues and organs (e.g., skin, liver, kidney, and lung).3 However, the role of hAECs in steatotic liver HIR injury has not been reported. Here, our results showed that hAECs could ameliorate HIR injury of steatotic livers through modulating p21-activated kinase 1 (PAK1)/AMP-activated protein kinase (AMPK)-dependent autophagy.

Despite the improvement of programmatic screening, adjuvant chemotherapy, and curative resection, colon cancer, with increasing incidence and mortality rates, still poses a significant public health challenge as the third most commonly diagnosed and second most fatal cancer worldwide.1 The myriad of benefits, encompassing the improved survival rates, treatment outcomes, and cost efficiency, further underscore the criticality of early colon cancer diagnosis. Hence, there is a pressing need to identify more potent biomarkers for improving the accuracy of colon cancer diagnosis. In summary, we identified three methylation-related biomarkers that exhibit excellent diagnostic performance, suggesting their significant potential for its application as noninvasive clinical biomarkers in the diagnosis of colon cancer.

Cervical cancer (CCa) is a substantial global health concern, and its lymph node metastasis (LNM) significantly diminishes patients' survival rates.1 Hence, a thorough investigation into the molecular mechanisms driving this progression is vital. Integrin alpha 2 (ITGA2) plays critical roles in various tumorigenic processes via cancer-related signaling pathways.2 In this study, we advanced the understanding of ITGA2's influence on CCa by revealing its role in promoting CCa LNM. Mechanistically, ITGA2 up-regulates SNAIL, instigating epithelial–mesenchymal transition (EMT) and activating the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, thereby augmenting CCa LNM. Remarkably, the inhibitor E7820, by down-regulating ITGA2 expression, shows promise in attenuating EMT and LNM of CCa. Therefore, E7820 could be developed as a potential therapeutic agent for the treatment of CCa LNM.

Ebola virus (EBOV) belongs to the Filoviridae family within the genus Ebolavirus and is responsible for the highly lethal hemorrhagic disease known as Ebola virus disease (EVD). The clinical manifestations of EVD include hemorrhagic fever, organ failure, and immune dysfunction.1 Liver damage is a significant contributor to mortality in EBOV-infected patients, and cell death plays a pivotal role in this process. Early reports indicated that EBOV infection could trigger multiple forms of cell death, and EBOV-induced hepatocyte apoptosis may be linked to liver injury, as liver conditions are significantly improved in Bim/Bid-deficient mice2 after EBOV infection. Choline-related metabolism plays an important role in cell membrane transportation and construction and is a significant indicator of cell injury.3 In the context of liver diseases associated with viruses, downstream metabolites of choline, such as fatty acids, serve as key indicators of long-term liver damage.4 Viral infection can lead to significant alterations in the host cell's internal environment, resulting in the accumulation of numerous folded and/or misfolded proteins originating from not only cells but also viruses within the endoplasmic reticulum (ER). Further investigation revealed that ER stress can trigger cell apoptosis through multiple signaling pathways.5 In summary, we investigated whether choline could attenuate EBOV infection and diminish apoptosis by reducing CHOP (C/EBP homologous protein) gene expression, revealing a novel mechanism by which EBOV induces host apoptosis.

The invasive micropapillary carcinoma (MPC) is a rare and specialized pathologic subtype of cancer. MPCs are highly aggressive, highly metastatic, and commonly associated with poor prognosis. MPC components have been found at least in breast, bladder, lung, ovary, parotid gland, stomach, and colorectum tumors. Morphologically, MPCs typically consist of small clusters of neoplastic cells with distinct polarity reversal and tight adhesion with each other, usually situating in the tumor invasion front.1 However, pure MPC tumors are extremely rare, MPCs commonly co-exist with other pathological fractions, such as adenocarcinoma, in tumor entity, and their proportion generally ranges from 5% to 95%.1 Although highly malignant, knowledge concerning the mechanisms underlying MPC behavior and critical events driving tumor progression toward MPC remains rather limited. Recently, two reports indicate that the copy-number loss of IGSF9 (immunoglobulin superfamily 9) and PRDM16 (PR domain containing 16) and copy-number gain of ALDH2 (aldehyde dedydrogenase-2) in breast MPCs are associated with high metastatic potential2 and that the aberrant activity of RhoA plays a critical role in polarity-switching in colorectal MPCs,3 respectively.

B-type natriuretic peptide (BNP) system is critical to cardiovascular physiological and pathological processes, especially in the development and progression of heart failure (HF) caused by dilated cardiomyopathy (DCM-HF).1,2 Single nucleotide polymorphism (SNP) in the non-coding region, especially the promoter region, might correlate well with plasma BNP levels, and potentially affect the susceptibility of DCM-HF, through interacting with transcription factor and regulating natriuretic peptide B (NPPB) gene transcription.3,4 Meanwhile, NPPB gene methylation might promote the process of DCM-HF development by dysregulating its gene transcription and affecting plasma BNP levels.5 This study demonstrated that: i) in all three SNP sites identified in the NPPB gene, mutational rs198389 in the promoter region promoted NPPB gene transcription through its combination with androgen receptor (AR); ii) as the critical transcription factor of NPPB gene, glucocorticoid receptor alpha (GR-ɑ) more obviously promoted NPPB gene transcription in combination with wild-type rs198389, and retinoid X receptor alpha (RXR-ɑ) more obviously inhibited NPPB gene transcription in combination with mutational rs198389; iii) NPPB gene methylation depressed NPPB gene transcription, and its demethylation accelerated NPPB gene unmethylation and transcription.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterized by hypophosphatemia, hypercalciuria, and recurrent nephrolithiasis, often resulting in rickets and osteomalacia.1 Mutations in the SLC34A3, which encodes the renal sodium-phosphate cotransporter NaPi-IIc, are the leading cause of HHRH. A case study of a 30-year-old female patient revealed she had compound heterozygous mutations in SLC34A3, including a novel intronic mutation, impacting gene splicing and reducing protein production. This underscores the critical role of SLC34A3 in HHRH and broadens the understanding of its genotypic and phenotypic diversity. Genetic diagnosis is crucial in identifying this rare disease, as active vitamin D is contraindicated in HHRH patients due to the associated hypercalciuria and nephrolithiasis.

Telomerase plays an essential role in the immortalization and stemness of cancer cells. PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) functions as a telomerase inhibitor and tumor suppressor.1 However, the underlying mechanism is still not clear. Here, we report the molecular basis of the tumor suppression function of PinX1. We determined the crystal structure of the TRFH (TRF homology) domain of TRF1 in complex with a short TRF1-binding motif of PinX1 and revealed that PinX1 bound to TRF1 via the F-X-L-X-P motif, providing a structural basis of how PinX1 is recruited to the telomeric region by TRF1. We demonstrated that PinX1 is directly associated with and inhibits telomerase activity by TID (telomerase inhibitory domain) with crucial lysine residues clustered in PinX1292-301. In cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), which is featured by short telomeres and high telomerase activity, PinX1-TID efficiently inhibits cancer stemness traits by primarily targeting telomerase activity. These findings provide valuable insights for developing strategies to treat cancers with short telomeres and advancing telomerase inhibitor therapeutics.

Accurate prediction of drug susceptibility is one of the most important steps in personalized medicine. Applications of machine learning to pharmacogenomic data for sensitivity prediction can help study the mechanism of drug response and find more effective anti-tumor drugs. At present, most machine learning algorithms for predicting the drug sensitivity of cancer cell lines involve gene-level characteristics. However, the auxiliary information of drugs has been proved to improve the prediction accuracy by providing a priori information for drug response. Here, we developed the WRE-XGBoost model, using gene expression of cell lines and drug properties as input, which consists of a weighted algorithm of the random forest regression and elastic net regression (WRE) to select the important features and an improved XGBoost algorithm associating with particle swarm optimization to predict cell viability (Fig. S1). The experimental results of our model were superior to frequently used machine learning methods through cross-validation.

Ovarian cancer is one of the leading causes of cancer-related deaths in women worldwide, with a five-year overall survival rate of less than 50% or 30% if it is in the advanced stages.1 Reactive oxygen species (ROS) are typically involved in signal transduction and gene activation.2 Recent studies suggest increased levels of ROS in cancer development,3,4 but the role and mechanism of ROS in ovarian cancer angiogenesis and development remain to be elucidated. Our study found much higher levels of ROS and C-X-C motif chemokine ligand 8 (CXCL8) in ovarian cancer cells and tumor tissues. ROS-induced CXCL8 up-regulation through glycogen synthase kinase-3 beta (GSK-3β) inactivation and p70S6 kinase 1 (p70S6K1) activation. There were strong positive correlations between expression levels of CXCL8 and p-GSK-3β/p-p70S6K1, showing that p-GSK-3β and p-p70S6K1 levels were important in CXCL8 expression in ovarian cancer. Furthermore, inhibition of p70S6K1 using its inhibitor PF-4708671 greatly increased the cytotoxic effect of platinum. ROS and CXCL8 are potential new therapeutic target(s) and biomarker(s) for ovarian cancer development in the future.

Obesity related metabolic diseases, including non-alcoholic fatty liver disease, insulin resistance, hyperglycemia, and hyperlipemia, have become major chronic diseases.1,2 As an important enzyme for ATP production,3 ATP5b plays a role in many diseases, including cancer, bone homeostasis, and microvascular proliferation.4,5 This study was conducted to investigate the role of ATP5b in glucose and lipid metabolism. Results showed that expression of Atp5b was markedly reduced in diet-induced obese mice and pigs. Heterozygote Atp5b knockout (Atp5b+/−) mice had lower body weight, adipose tissue weight, and triglyceride content in both serum and the liver than their wild-type (WT) littermates under high-fat diet conditions. Furthermore, gene expression of Atgl in the liver and adipose tissue was higher in Atp5b+/− mice than in WT mice.

The SET-NUP214 gene fusion is mainly found in patients primarily diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) and rarely in acute myeloid leukemia (AML).1 Patients with the SET-NUP214 fusion protein (referred to as SN-214) have poor responses to allogeneic stem cell transplantation and a three-year disease-free survival rate of less than 40%.2 At the molecular level, the SN-214 fusion is known to recruit chromosomal region maintenance 1 (CRM1) and disruptor of telomeric silencing 1-like (DOT1L) proteins to the promoters of homeobox (HOX)-cluster genes, which is consistent with the overexpression of these genes in SN-214+ T-ALL.1 In contrast, silencing of the tumor suppressor gene, TET methylcytosine dioxygenase 2 (TET2), has been observed in the SN-214+ T-ALL cell line LOUCY due to hypermethylation at the promoter.3 However, the mechanism by which SN-214 alters the DNA methylation (DNAm) landscape to regulate leukemic transcriptional programs and signaling cascades, particularly in the myeloid lineage of leukemia, remains unexplored. Due to the rarity of the disease and the unavailability of genomic data from primary AML samples, our study focused on the MEGAL (ACC719, DSMZ) cell line. This cell line was identified as the only AML cell line expressing SN-214, and we used it to investigate the role of DNAm in leukemic transcriptional programs. To capture genome-wide DNAm and expression, we used the Infinium MethylationEPIC v2.0 BeadChip array and RNA sequencing, respectively. Considering the megakaryoblastic (M7, FAB classification) lineage of the MEGAL cell line, we analyzed the epigenetic changes in comparison to CD41+ megakaryocyte (MK) progenitors differentiated from umbilical cord blood-derived CD34+ hematopoietic stem progenitor cells (HSPC). We also analyzed the chromatin immunoprecipitation-sequencing data from the LOUCY cell line to identify possible overlaps of the transcription factor CTCF and chromatin marks (H3K4me1, H3K4me3, H3K27ac, H3K36me3, and H3K27me3) with differentially methylated CpGs (mC) in MEGAL. This integrative epigenetic analysis helped us understand the impact of the SN-214 fusion on leukemic transcriptional programs.

Endometrial cancer (EC) is one of the most common gynecological malignant tumors. Further investigation of the potential molecular mechanism of EC is important. Small nucleolar RNA (snoRNA) is a type of non-coding RNA, with an unclear biological function in EC. We found that Box C/D snoRNA SNORD3B-2 participated in EC oncogenesis and development via the PI3K-AKT signaling pathway. RNA immunoprecipitation (RIP) revealed that SNORD3B-2 bound to polo-like kinase 1 (PLK1) through fibrillin (FBL). RTL-P (reverse transcription at low dNTPs-PCR) and actinomycin D assays confirmed that SNORD3B-2 directed 2′-O-methylation modification of PLK1 mRNA, and the modification could promote the stability of PLK1 mRNA which could mediate tumor growth and metastasis in EC. Moreover, SNORD3B-2 overexpression was associated with retained Exon 3 of RAB17 thus activating the PI3K-AKT signaling pathway. This alternative splicing was achieved by SNORD3B-2 regulating the protein level of splice factor SF3B1 (splicing factor 3b subunit 1).

Sex-determining region Y-box protein 3 (SOX3) is a member of the SoxB1 transcription factors subfamily including SOX1 and SOX2, first identified based on homology to the high mobility box.1 The oncogenic potential of the high mobility group box protein SOX3 has been widely validated. However, there have been inconsistent reports of SOX3 expression in hepatocellular carcinoma (HCC). For example, Zhang et al showed that SOX3 mRNA levels were not significantly different between the tumor and its corresponding adjacent normal tissues.2 Contrarily, a noteworthy contrast was revealed by Li and colleagues,3 who reported an evident up-regulation of SOX3 expression in 188 HCC samples from the TCGA database, compared with 50 normal liver tissues.3 In contrast to these findings, Yang et al offered compelling evidence indicating the association of SOX3 with tumor progression and unfavorable prognosis in HCC.4 However, the specific role and mechanism of SOX3 in these reports had not been investigated.

Lung adenocarcinoma (LUAD) is the primary subtype of lung cancer, but its prognosis remains challenging. The tumor microenvironment plays a central role in the initiation and development of tumors, particularly regarding the composition of cell types. Understanding the cellular composition within tumors is crucial for comprehending disease processes and improving treatments. Single-cell RNA sequencing (scRNA-seq) provides high-resolution gene expression data for single cells within tumors, allowing for precise analysis of different cell types and their gene expression profiles, but it lacks prognostic information. In contrast, bulk RNA sequencing (bulk RNA-seq) data contains plenty of prognostic information. Therefore, the deconvolution of scRNA-seq combined with bulk RNA-seq containing prognostic information is a favorable approach. In this study, we discovered a positive correlation between a high proportion of tumor-infiltrating plasma cells (PCs) and improved overall survival in LUAD. Through bioinformatics analysis, we identified TNFRSF17 as a potential key factor to improve prognosis in LUAD. This discovery was validated through immunohistochemical staining of clinical samples, suggesting that TNFRSF17 plays a pivotal role in the underlying mechanisms affecting LUAD prognosis.

Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor, and amplified human epidermal growth factor receptor expression. TNBC accounts for ∼15% of all breast cancer cases but represents >50% of breast cancer (BC)-related mortalities.1 There is an urgent need for biomarkers that can predict the metastatic potential of TNBC and be used as prognostic indicators or targets for treatment. Transmembrane protein family 132E (TMEM132E, T132E) belongs to the TMEM132 family which encodes single-pass type I transmembrane proteins and consists of TMEM132A, B, C, D, and E.2 The TMEM132 genes have been implicated in various cancers. Single nucleotide polymorphism association analysis suggests that T132E may increase the risk of BC in women undergoing menopausal hormone therapy.3 Few studies have explored the role of TMEM132E in BC, particularly TNBC.

Invasive mucinous lung adenocarcinoma (IMA) is an aggressive subtype characterized by the presence of tumor cells with goblet cell morphology and abundant intracytoplasmic mucin. A previous study had shown that all epithelial tumors share similar gene expression-based luminal/basal subtypes and can impact treatment response.1 We identified the subtype of mucinous adenocarcinoma and found that many of them exhibit a luminal phenotype, particularly IMA. We established a single-cell atlas of the transition from lung adenocarcinoma (LUAD) to IMA and found that the luminal phenotype of IMA is characterized by high expression of FOXA1 and specific enrichment of the extracellular matrix (ECM)-receptor interaction pathway. CellChat analysis revealed that the SPP1-CD44 axis mediated communication between IMA and M2 macrophages. By chromatin immunoprecipitation sequencing analysis, we observed consistent enrichment of differential histone modifications at the ECM pathway. The luminal subtype marker FOXA1 is central to the luminal-associated transcriptional programs and may bind to super-enhancer regions near EHF and promote its expression. Furthermore, EHF can bind to the transcription start site region of the prognostic risk factor ITGB4 and promote its expression. Overall, the luminal-associated transcriptional programs (FOXA1-EHF-ITGB4) and its downstream ECM-receptor interaction pathway (SPP1, CD44, ITGB4) play a crucial role in IMA, influencing its immunity and tumor risk (Fig. 1A).

Gemcitabine is widely used in the treatment of pancreatic ductal adenocarcinoma (PDAC), but the development of chemoresistance poses a significant challenge to achieving long-term disease-free survival in PDAC patients.1 Resistance to gemcitabine may arise from various cellular and molecular changes in metabolism, tumor microenvironment, and DNA damage repair efficiency.2 Despite existing knowledge, large-scale molecular mechanisms underlying gemcitabine resistance remain unclear. Understanding these mechanisms could lead to more effective treatment strategies for this highly aggressive disease.

The KCNH7 (Potassium Voltage-Gated Channel Subfamily H Member 7) gene belongs to the Ether-A-Go-Go-Related Gene (ERG) subfamily of voltage-gated potassium channels. There are three members of the ERG family: ERG1, ERG2 and ERG3, with the latter being encoded by the KCNH7 gene. ERG1 is highly expressed in cardiomyocytes, and its mutations have been linked to arrhythmias, such as the long QT syndrome.1 Research on ERG2 is limited, while ERG3 is primarily expressed in neurons. The connection between the KCNH7 gene and neurological disorders remains to be elucidated.

Photodynamic therapy is an “old” strategy for cancer therapy featuring clinical safety and rapid working, but suitable photosensitizers for colorectal cancer therapy remain lacking. This study synthesized a novel photosensitizer termed Ce6-GFFY based on a self-assembling peptide GFFY and a photo-responsive molecule chlorin e6 (Ce6). Ce6-GFFY forms macroparticles with a diameter of ∼160 nm and possesses a half-life of 10 h, as well as an ideal tumor-targeting ability in mouse models. Ce6-GFFY effectively penetrates cells and generates numerous reactive oxygen species upon 660 nm laser irradiation. The reactive oxygen species promotes the accumulation of cytotoxic T cells and decrease of myeloid-derived suppressor cells in the tumor microenvironment through immunogenic cell death, thus prohibiting the growth of both primary and metastatic tumors after once treatment. This study not only provides a strategy for photosensitizer development but also confirms a promising application of Ce6-GFFY for colorectal cancer therapy.

Macrophages play a key role in wound healing. Dysfunction of their M0 polarization to M2 leads to disorders of the wound immune microenvironment and chronic inflammation, which affects wound healing. Regulating the polarization of M0 macrophages to M2 macrophages is an effective strategy for treating wound healing. Mesenchymal stem cells (MSCs) deliver endogenous regulatory factors via paracrine extracellular vesicles, which may play a key role in wound healing, and previous studies have shown that apoptotic bodies (ABs) are closely associated with inflammation regression and macrophage polarization. However, the specific regulatory mechanisms involved in ABs remain unknown. In the present study, we designed an MSC-AB (MSC-derived AB)-loaded polycaprolactone (PCL) scaffold, evaluated the macrophage phenotype and skin wound inflammation in vivo and in vitro, and explored the ability of MSC-AB-loaded PCL scaffolds to promote wound healing. Our data suggest that the PCL scaffold regulates the expression of the CCL-1 gene by targeting the delivery of mmu-miR-21a-5p by local sustained-release MSC-ABs, and drives M0 macrophages to program M2 macrophages to regulate inflammation and angiogenesis, thereby synergistically promoting wound healing. This study provides a promising therapeutic strategy and experimental basis for treating various diseases associated with imbalances in proinflammatory and anti-inflammatory immune responses.

Orthodontic tooth movement (OTM) depends on periodontal ligament cells (PDLCs), which sense biomechanical stimuli and initiate alveolar bone remodeling. Light (optimal) forces accelerate OTM, whereas heavy forces decelerate it. However, the mechanisms by which PDLCs sense biomechanical stimuli and affect osteoclastic activities under different mechanical forces (MFs) remain unclear. This study demonstrates that mechanosensitive ion channel Piezo1-mediated Ca2+ signal conversion is crucial for sensing and delivering biomechanical signals in PDLCs under heavy-force conditions. Heavy MF up-regulated Piezo1 in PDLCs, reducing mitochondrial Ca2+ influx by inhibiting ITPR3 expression in mitochondria-associated membranes. Decreased mitochondrial calcium uptake led to reduced cytoplasmic release of mitochondrial DNA and inhibited the activation of the cGAS‒STING signaling cascade, subsequently inhibiting monocyte-to-osteoclast differentiation. Inhibition of Piezo1 or up-regulation of STING expression under heavy MF conditions significantly increased osteoclast activity and accelerated OTM. These findings suggest that heavy MF-induced Piezo1 expression in PDLCs is closely related to the control of osteoclast activity during OTM and plays an essential role in alveolar bone remodeling. This mechanism may be a potential therapeutic target for accelerating OTM.

Although the pathogenesis and mechanism of congenital skeletal dysplasia are better understood, progress in drug development and intervention research remains limited. Here we report that melatonin treatment elicits a mitigating effect on skeletal abnormalities caused by SLC26A2 deficiency. In addition to our previous finding of endoplasmic reticulum stress upon SLC26A2 deficiency, we found calcium (Ca2+) overload jointly contributed to SLC26A2-associated chondrodysplasias. Continuous endoplasmic reticulum stress and cytosolic Ca2+ overload in turn triggered apoptosis of growth plate chondrocytes. Melatonin, known for its anti-oxidant and anti-inflammatory properties, emerged as a promising therapeutic approach in our study, which enhanced survival, proliferation, and maturation of chondrocytes by attenuating endoplasmic reticulum stress and Ca2+ overload. Our findings not only demonstrated the efficacy of melatonin in ameliorating abnormal function and cell fate of SLC26A2-deficient chondrocytes in vitro but also underscored its role in partially alleviating the skeletal dysplasia seen in Col2a1-CreERT2; Slc26a2fl/fl mice. As revealed by histology and micro-CT analyses, melatonin significantly improved retarded cartilage growth, defective trabecular bone formation, and tibial genu varum in vivo. Collectively, these data shed translational insights for drug development and support melatonin as a potential treatment for SLC26A2-related chondrodysplasias.

Hepatic ischemia-reperfusion injury is an unavoidable surgical complication of liver transplantation and the leading cause of poor graft function and increased mortality post-transplantation. Multiple mechanisms have been implicated in ischemia-reperfusion injury; however, the characteristic changes at the transcriptional and metabolic levels in the early, intermediate, and late phases of ischemia-reperfusion injury remain unclear. In the study, mice underwent laparotomy following anesthesia, and the blood vessels of the liver were clipped using a vascular clamp to form 70% warm ischemia of the liver. Mouse liver sections and serum samples were collected and divided into the Sham, I1R12, I1R24, and I1R48 groups. Transcriptomics and metabolomics analyses were performed to study characteristic alterations during the early, intermediate, and late phases of ischemia-reperfusion injury. Quantitative real-time PCR was used to validate the critical differentially expressed genes. The differentially expressed genes and metabolites were identified by transcriptomics and metabolomics analyses. Moreover, GO and KEGG enrichment analyses indicated that glucose metabolism remodeling, inflammatory response activation, and lipid metabolism remodeling were characteristic changes in the early, intermediate, and late phases of ischemia-reperfusion injury, respectively. In summary, our study revealed the importance of glucolipid metabolism in ischemia-reperfusion injury and provided potential therapeutic intervention targets and a new perspective to explore the underlying mechanisms of ischemia-reperfusion injury.

Cancer-associated cachexia (CAC) is a severe metabolic disorder syndrome mainly characterized by muscle and fat loss, which accounts for one-third of cancer-related deaths. No effective therapeutic approach that could fully reverse CAC is available. NF-κB signaling and oxidative stress play vital roles in both muscle atrophy and fat loss in CAC. Here, we showed that our developed oral compound Z526 exhibited potent anti-CAC efficacy by inhibiting NF-κB signaling and ameliorating oxidative stress. In vitro, Z526 alleviated C2C12 myotube atrophy and 3T3-L1 adipocyte lipolysis induced by conditioned mediums of multiple cachectic tumor cells or pro-cachectic inflammatory cytokines. In vivo, Z526 attenuated the cachectic symptoms of C26 or LLC tumor-bearing mice. Z526 treatment reduced weight loss without impacting tumor growth and improved muscle atrophy, fat loss, and impaired grip force. Besides, serum TNF-α and IL-6 levels were reduced after Z526 treatment in C26 tumor-bearing mice. Of note, Z526 significantly prolonged the survival of LLC tumor-bearing mice. Activated NF-κB signaling and oxidative stress in cachectic muscle and fat tissues were reversed by Z526. Furthermore, Z526 exhibited a promising preclinical safety profile. Thus, oral Z526, which exhibited potent anti-CAC activities in vitro and in vivo, multiple interventions in diverse pathogenic mechanisms (NF-κB signaling and oxidative stress), and a favorable preclinical safety profile, holds the promise to be developed into a novel and beneficial therapeutic option for CAC.

Peritoneal dissemination frequently develops in patients with ovarian cancer (OC) and is associated with recurrence and metastasis. However, the cellular components and mechanisms supporting OC peritoneal metastasis are poorly understood. To elucidate these, we utilized RNA sequencing to investigate the cellular composition and function. Insights from transcriptome analyses suggested that OC cells from malignant ascites persisted in a quiescent state of low metabolic activity and after metastases to the peritoneum, arrested OC cells were reactivated and induced back to the cell cycle, suggesting that the peritoneum served as a favor tumor microenvironment. To elucidate the mechanisms, we then developed long-range migration and competitive inhibition assays and showed that peritoneal adipose-derived stem cells-derived extracellular vesicles (ADSCs-EVs) mediated preferential migration of OC cells toward peritoneal ADSCs but not other representative cells from the peritoneal cavity. In line with phenotypic changes, transcriptomic analysis revealed that patient peritoneal ADSCs-EVs stimulated the expression of numerous genes associated with OC cell proliferation and migration; among them, the epidermal growth factor receptor (EGFR) and nuclear factor kappa B (NF-κB) signaling pathways were highly enriched. We also found that peritoneal ADSCs produced and secreted key EGFR signaling molecules, including EGF and EGFR, into ADSCs-EVs. Upon fusion with OC cells, ADSCs-EVs up-regulated the EGFR-NF-κB axis and promoted OC cell proliferation and migration. Interference with either ADSCs-EVs production or EGFR signaling abolished the proliferation and migration effect. The results show that ADSCs modulate OC cell proliferation and migration at multiple layers, constituting a key mechanism in OC progression.

Chondrocyte is considered the only cell type in cartilage. However, the cell heterogeneity of chondrocytes in human articular cartilage is still not well defined, which hinders our understanding of the pathogenesis of osteoarthritis (OA). Here, we constructed a single-cell transcriptomic atlas of chondrocytes in healthy cartilage and identified nine chondrocyte subsets including homeostatic chondrocytes, proliferate fibrochondrocytes, and hypertrophic chondrocytes (HTC). Interestingly, we identified two distinct HTC subpopulations, among which HTC-1 specifically expressed genes associated with apoptosis and programmed cell death. We identified two main trajectories of chondrocytes, one of which differentiates into fibrochondrocytes, while the other terminates in apoptosis. Comparison of chondrocyte subsets between healthy and OA cartilage showed that proliferate fibrochondrocytes and HTC-1 expanded in OA patients, whereas homeostatic chondrocytes decreased. Interestingly, we discovered an OA-specific proliferate fibrochondrocyte subset that may contribute to the development of OA via inflammation. In summary, this study significantly enhanced our understanding of cell heterogeneity of chondrocytes in articular cartilage and provides insight into the pathogenesis of OA.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions containing aggregated α-synuclein (α-Syn). While the pathology of PD is multifaceted, the aggregation of α-Syn and mitochondrial dysfunction are well-established hallmarks in its pathogenesis. Recently, TFE3, a transcription factor, has emerged as a regulator of autophagy and metabolic processes. However, it remains unclear whether TFE3 can facilitate the degradation of α-Syn and regulate mitochondrial metabolism specifically in dopaminergic neurons. In this study, we demonstrate that TFE3 overexpression significantly mitigates the loss of dopaminergic neurons and reduces the decline in tyrosine hydroxylase-positive fiber density, thereby restoring motor function in an α-Syn overexpression model of PD. Mechanistically, TFE3 overexpression reversed α-Syn-mediated impairment of autophagy, leading to enhanced α-Syn degradation and reduced aggregation. Additionally, TFE3 overexpression inhibited α-Syn propagation. TFE3 overexpression also reversed the down-regulation of Parkin, promoting the clearance of accumulated mitochondria, and restored the expression of PGC1-α and TFAM, thereby enhancing mitochondrial biogenesis in the adeno-associated virus-α-Syn model. These findings further underscore the neuroprotective role of TFE3 in PD and provide insights into its underlying mechanisms, suggesting TFE3 as a potential therapeutic target for PD.

Aging is an independent risk factor for cardiovascular diseases. Cardiac diastolic dysfunction (CDD), ultimately leading to heart failure with preserved ejection fraction (HFpEF), is prevalent among older individuals. Although therapeutics have made great progress, preventive strategies remain unmet medical needs. Green tea catechins have been shown to be effective in improving aging-related cardiovascular and cerebral disorders in animal models and patients. However, little attention has been paid to whether long-term administration of epigallocatechin gallate (EGCG), the major bioactive ingredient of green tea catechins, could prevent the onset and progression of CDD. In this study, 12-month-old female mice were orally administered 50, 100 and 200 mg EGCG mixed with drinking water for 6 months. Aged mice (18 months old) exhibited the major features of HFpEF, including CDD with pEF, cardiac fibrosis, increased cardiomyocyte apoptosis, and mitochondrial damages, as well as elevated A/B-type natriuretic peptide. Cardiac troponin I (cTnI) expression was also reduced. Long-term administration of 100 or 200 mg EGCG prevented aging-related CDD and exercise capacity decline, along with alleviating myocardial apoptosis and mitochondria damage. The transcription and protein expression of cTnI were increased, which might be achieved by inhibiting the expression and activity of histone deacetylase 1 (HDAC1), and reducing its binding level near cTnI's promoter, thereby elevating acetylated histone 3 (AcH3) and acetylated lysine 9 on histone H3 (AcH3K9) in the aged mice. We provide a novel insight that long-term administration of EGCG is a potentially effective strategy in preventing aging-related CDD and cTnI expression decline.

Family with sequence similarity 20 C (FAM20C) is a Golgi protein kinase that phosphorylates the serine residue in the S-x-E/pS motif of target proteins. FAM20C phosphorylates most secreted proteins, which play important roles in multiple biological processes, including cancer progression, biomineralization, and lipid homeostasis. Numerous studies have documented the potential contribution of FAM20C to the growth, invasion, and metastasis of glioma, breast cancer, and other cancers, as well as to the mineralization process of teeth and bone. In addition, FAM20C has been found to be associated with the occurrence and development of certain cardiovascular diseases and endocrine metabolism disorders. It raises hopes that understanding the disease-specific mechanisms of FAM20C may hold the key to developing new strategies for these diseases. This review comprehensively covers the existing literature to provide a summary of the structure and biological functions of FAM20C, with a particular focus on its roles in the disease context.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy characterized by insidious onset and lack of effective therapy. The molecular pathogenesis of PDA remains to be understood fully. Transcriptional factor GATA6 is an important transcriptional regulator in normal pancreas development, particularly in the initial specification and differentiation of the pancreas. Recent studies have linked pancreatic malignancy closely to GATA6. Increased levels of GATA6 expression enhance pancreatic cancer cell growth. GATA6 emerges as a lineage-specific oncogenic factor in PDA, augmenting the oncogenic phenotypes of PDA cells upon its overexpression. However, elevated GATA6 levels are correlated with well-differentiated tumors and a more favorable patient prognosis. Experimental evidence in genetic mouse models has revealed a tumor-suppressive role for GATA6. The circumstantial roles of GATA6 in pancreatic tumorigenesis remain to be defined. This review aims to elucidate recent advances in comprehending GATA6, emphasizing its crucial roles in both pancreas physiology and pathology. Special attention will be given to its involvement in PDA pathogenesis, exploring its potential as a novel biomarker and a promising therapeutic target for PDA.

Genetic alterations to serine-threonine kinase 11 (STK11) have been implicated in Peutz-Jeghers syndrome and tumorigenesis. Further exploration of the context-specific roles of liver kinase B1 (LKB1; encoded by STK11) observed that it regulates AMP-activated protein kinase (AMPK) and AMPK-related kinases. Given that both migration and proliferation are enhanced with the loss of LKB1 activity combined with the prevalence of STK11 genetic alterations in cancer biopsies, LKB1 was marked as a tumor suppressor. However, the role of LKB1 in tumorigenesis is paradoxical as LKB1 activates autophagy and reactive oxygen species scavenging while dampening anoikis, which contribute to cancer cell survival. Due to the pro-tumorigenic properties of LKB1, targeting LKB1 pathways is now relevant for cancer treatment. With the recent successes of targeting LKB1 signaling in research and clinical settings, and enhanced cytotoxicity of chemical compounds in LKB1-deficient tumors, there is now a need for LKB1 inhibitors. However, validating LKB1 inhibitors is challenging as LKB1 adaptor proteins, nucleocytoplasmic shuttling, and splice variants all manipulate LKB1 activity. Furthermore, STE-20-related kinase adaptor protein (STRAD) and mouse protein 25 dictate LKB1 cellular localization and kinase activity. For these reasons, prior to assessing the efficacy and potency of pharmacological candidates, the functional status of LKB1 needs to be defined. Therefore, to improve the understanding of LKB1 in physiology and oncology, this review highlights the role of LKB1 in tumorigenesis and addresses the therapeutic relevancy of LKB1 inhibitors.

The tumor microenvironment is a complex environment comprising tumor cells, non-tumor cells, and other critical non-cellular components. Some studies about tumor microenvironment have recently achieved remarkable progress in tumor treatment. As a substantial part of post-translational protein modification, ubiquitination is a crucial player in maintaining protein stability in cell signaling, cell growth, and a series of cellular life activities, which are also essential for regulating tumor cells or other non-tumor cells in the tumor microenvironment. This review focuses on the role and function of ubiquitination and deubiquitination modification in the tumor microenvironment while discussing the prospect of developing inhibitors targeting ubiquity-related enzymes, thereby providing ideas for future research in cancer therapy.

Diabetic nephropathy is a prevalent complication of diabetes and stands as the primary contributor to end-stage renal disease. The global prevalence of diabetic nephropathy is on the rise, however, due to its intricate pathogenesis, there is currently an absence of efficacious treatments to enhance renal prognosis in affected patients. The mammalian target of rapamycin (mTOR), a serine/threonine protease, assumes a pivotal role in cellular division, survival, apoptosis delay, and angiogenesis. It is implicated in diverse signaling pathways and has been observed to partake in the progression of diabetic nephropathy by inhibiting autophagy, promoting inflammation, and increasing oxidative stress. In this academic review, we have consolidated the understanding of the pathological mechanisms associated with four distinct resident renal cell types (podocytes, glomerular mesangial cells, renal tubular epithelial cells, and glomerular endothelial cells), as well as macrophages and T lymphocytes, within a diabetic environment. Additionally, we highlight the research progress in the treatment of diabetic nephropathy with drugs and various molecules interfering with the mTOR signaling pathway, providing a theoretical reference for the treatment and prevention of diabetic nephropathy.

Phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of a p110 catalytic subunit and a p85 regulatory subunit. The PIK3CA gene, which encodes the p110α, is the most frequently mutated oncogene in cancer. Oncogenic PIK3CA mutations activate the PI3K pathway, promote tumor initiation and development, and mediate resistance to anti-tumor treatments, making the mutant p110α an excellent target for cancer therapy. PIK3CA mutations occur in two hotspot regions: one in the helical domain and the other in the kinase domain. The PIK3CA helical and kinase domain mutations exert their oncogenic function through distinct mechanisms. For example, helical domain mutations of p110α gained direct interaction with insulin receptor substrate 1 (IRS-1) to activate the downstream signaling pathways. Moreover, p85β proteins disassociate from helical domain mutant p110α, translocate into the nucleus, and stabilize enhancer of zeste homolog 1/2 (EZH1/2). Due to the fundamental role of PI3Kα in tumor initiation and development, PI3Kα-specific inhibitors, represented by FDA-approved alpelisib, have developed rapidly in recent decades. However, side effects, including on-target side effects such as hyperglycemia, restrict the maximum dose and thus clinical efficacy of alpelisib. Therefore, developing p110α mutant-specific inhibitors to circumvent on-target side effects becomes a new direction for targeting PIK3CA mutant cancers. In this review, we briefly introduce the function of the PI3K pathway and discuss how PIK3CA mutations rewire cell signaling, metabolism, and tumor microenvironment, as well as therapeutic strategies under development to treat patients with tumors harboring a PIK3CA mutation.

Pdgfrα+ stromal cells are a group of cells specifically expressing Pdgfrα, which may be mentioned with distinct names in different tissues. Importantly, the findings from numerous studies suggest that these cells share exactly similar biomarkers and properties, show complex functions in regulating the microenvironment, and are critical to tissue regeneration, repair, and degeneration. Comparing the similarities and differences between distinct tissue-resident Pdgfrα+ stromal cells is helpful for us to more comprehensively and deeply understand the behaviors of these cells and to explore some common regulating mechanisms and therapeutical targets. In this review, we summarize previous and current findings on Pdgfrα+ stromal cells in various tissues and discuss the crosstalk between Pdgfrα+ stromal cells and microenvironment.

DNA exonucleases and endonucleases are key executors of the genome during many physiological processes. They generate double-stranded DNA by cleaving damaged endogenous or exogenous DNA, triggering the activation of the innate immune pathways such as cGAS-STING-IFN, and enabling the body to produce anti-viral or anti-tumor immune responses. This is of great significance for maintaining the stability of the genome and improving the therapeutic efficacy of tumors. In addition, genomic instability caused by exonuclease mutations contributes to the development of various autoimmune diseases. This review summarizes the DNA exonucleases and endonucleases which have critical functions in immunity and associated diseases.