Adipose tissue-derived mesenchymal stem cells (ADSCs) are identified to be potential therapeutic candidates for diabetic nephropathy (DN) through secreting exosomes (Exos). Ubiquitin-specific protease 25 (USP25) has been reported to be involved in DN-induced renal injury. Herein, this study aimed to investigate whether ADSCs affected DN progression by Exo transfer of USP25. High glucose (HG)-induced mouse podocytes were used to mimic DN-induced injury for in vitro viability, inflammation, and apoptosis analyses. The db/db mice of DN were established for renal injury and function analysis in vivo. The deubiquitination effect of USP25 was analyzed by cellular ubiquitination and immunoprecipitation assays. ADSCs reversed HG-induced apoptosis and inflammation in podocytes, and these effects were achieved by Exo-mediated transfer of USP25. Mechanistically, USP25 interacted with SMAD7 protein and elevated its expression in podocytes via inducing SMAD7 deubiquitination. USP25 transferred via ADSC-Exos abolished HG-induced apoptosis and inflammation in podocytes by elevating SMAD7 protein levels. In vivo assay also confirmed that ADSC-Exo attenuated Type 2 Diabetes Mellitus-induced kidney injury and podocyte apoptosis and inflammation by releasing USP25. ADSCs attenuated T2DM-induced kidney injury, podocyte apoptosis, and inflammation via elevating SMAD7 stabilization through exosome transfer of USP25.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, with a prevalence as high as 32.4%. MASLD encompasses a spectrum of liver pathologies, ranging from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and, in some cases, progression to end-stage liver disease (cirrhosis and hepatocellular carcinoma). A comprehensive understanding of the pathogenesis of this highly prevalent liver disease may facilitate the identification of novel targets for the development of improved therapies. E3 ubiquitin ligases and deubiquitinases (DUBs) are key regulatory components of the ubiquitin‒proteasome system (UPS), which plays a pivotal role in maintaining intracellular protein homeostasis. Emerging evidence implicates that aberrant expression of E3 ligases and DUBs is involved in the progression of MASLD. Here, we review abnormalities in E3 ligases and DUBs by (1) discussing their targets, mechanisms, and functions in MASLD; (2) summarizing pharmacological interventions targeting these enzymes in preclinical and clinical studies; and (3) addressing challenges and future therapeutic strategies. This review synthesizes current evidence to highlight the development of novel therapeutic strategies based on the UPS for MASLD and progressive liver disease.

The ubiquitin-proteasome system (UPS) is a major pathway of specific intracellular protein degradation through proteasome degradation of ubiquitin-labeled substrates. Numerous biological processes, including the cell cycle, transcription, translation, apoptosis, receptor activity, and intracellular signaling, are regulated by UPS. Alterations of the UPS, which render them more or less susceptible to degradation, are responsible for disorders of renal diseases. This review aims to summarize the mechanism of UPS in renal diseases. Besides, this review explores the relationship among UPS, autophagy, and deubiquitination in the development of renal disease. The specific molecular linkages among these systems and pathogenesis, on the other hand, are unknown and controversial. In addition, we briefly describe some anti-renal disease agents targeting UPS components. This review emphasizes UPS as a promising therapeutic modality for the treatment of kidney disease. Our work, though still basic and limited, could provide options to future potential therapeutic targets for renal diseases with a UPS underlying basis.

Renal tubular injury was a significant pathological change of diabetic kidney disease (DKD), and the amelioration of renal tubular injury through mitochondrial function was an important treatment strategy of DKD. Our previous study had revealed that Jujuboside A (Ju A), the main active substance isolated from Semen Ziziphi Spinosae (SZS), could restore renal function of diabetic mice. However, its protective mechanism against DKD remains unclear.

To investigate the effects and the mechanism of Ju A against DKD-associated renal tubular injury.

The anti-apoptotic effect of Ju A and its protection effect on mitochondria dysfunction of renal tubular epithelial cells (RTECs) were examined in high glucose (HG)-cultured HK-2 cells, and in db/db mice. Subsequently, Network Pharmacology analysis, molecular docking, luciferase assay, chromatin immunoprecipitation (ChIP), Yin Yang 1 (YY1) overexpression lentiviral vector and peroxisome proliferator-activated receptor-γ coactlvator-1α (PGC-1α) specific agonist ZLN005 were all used to identify the protective mechanism of Ju A towards DKD-associated mitochondrial dysfunction of RTECs.

Ju A inhibited RTECs apoptosis and ameliorated mitochondria dysfunction of RTECs of diabetic mice, and HG-cultured HK-2 cells. YY1 was the potential target of Ju A against DKD-related mitochondrial dysfunction, and the down-regulation of YY1 induced by Ju A increased PGC-1α promoter activity, leading to the restored mitochondrial function of HG-treated HK-2 cells. Renal tubule specific overexpression of YY1 intercepted the renal protective effect of Ju A on diabetic mice via blocking PGC-1α-mediated restoration of mitochondrial function of RTECs. The in-depth mechanism research revealed that the protective effect of Ju A towards DKD-associated renal tubular injury was linked to the restored mitochondrial function through YY1/PGC-1α signaling, resulting in the inhibited apoptosis of RTECs in diabetic condition via inactivating CytC-mediated Caspase9/Caspase3 signaling.

Ju A through the inhibition of mitochondria-dependent apoptosis alleviated DKD-associated renal tubular injury via YY1/PGC-1α signaling.

Diabetic retinopathy (DR) is a common complication of diabetes that can lead to poor vision and blindness. This study aimed to explore the mechanism of action of miR-130a-3p in DR progression.

In this study, we administered a single intraperitoneal injection of 100 mg/kg streptozotocin (STZ) to construct a DR mouse model, and induced a human monocyte cell line (THP-1) to differentiate into M0 macrophages, after which the M0 macrophages were cultured with 30 mM high glucose (HG) as a model of inflammation. The relative gene and protein levels were validated by RT-qPCR and western blotting. Macrophage polarization and retinal damage in the mice were tested using ELISA, MDC staining, immunofluorescence staining, and HE staining.

The results revealed that the expression of miR-130a-3p was low in M1 macrophages, whereas the expression of miR-130a-3p was high in M2 macrophages, and the level of miR-130a-3p was reduced after HG treatment of macrophages. The overexpression of miR-130a-3p attenuated HG- or STZ-induced inflammation, promoted macrophage autophagy, inhibited M1 polarization of macrophages, and attenuated the progression of DR. In addition, YY1 was the downstream target gene of miR-130a-3p, and overexpression of miR-130a-3p inhibited YY1 expression. However, overexpression of YY1 weakened the effect of miR-130a-3p mimic. After further treatment with the PI3K/Akt/mTOR pathway activator 740 Y-P, the effect of YY1 knockdown was weakened, macrophage autophagy was inhibited, and M1 polarization and inflammation were promoted.

miR-130a-3p inhibited the activation of the PI3K/Akt/mTOR pathway by downregulating YY1 expression, thus facilitating macrophage autophagy, inhibiting M1 polarization and the inflammatory response of macrophages, and finally attenuating the progression of DR. The results of this study provide theoretical support for the use of miR-130a-3p as a new target for the treatment of DR.

Diabetic kidney disease2 (DKD) is a chronic complication of diabetes characterized by kidney damage due to persistent hyperglycemia. A growing number of evidence indicated that circular RNAs3 (circRNAs) play a crucial role in diabetes and associated complications. However, the function and mechanism of circRNAs in DKD remain unclear. Herein, we investigated the expression profiles of circRNAs in DKD mice compared to non-diabetic mice using RNA-seq analysis. A novel circRNA, circMRP4, derived from the circularization of Multidrug resistance-associated protein 44 (MRP4) was identified. The expression of circMRP4 was significantly increased in both kidney tissues of DKD and mouse podocytes exposed to high glucose5 (HG). In addition, knockdown of circMRP4 alleviated podocytes apoptosis and inflammation induced by HG, while circMRP4 overexpression resulted in the opposite impact. Dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assay demonstrated that circMRP4 could directly target miR-499-5p which was closely associated with podocytes apoptosis and inflammation. Furthermore, circMRP4 was found to act as a sponge for miR-499-5p, leading to the upregulation of its target RRAGB, thereby activating the mTORC1/P70S6K signaling. In summary, our findings suggested that circMRP4 mediated podocytes apoptosis and inflammation in DKD by modulating the miR-499-5p/RRAGB/mTORC1/P70S6K axis, highlighting circMRP4 as a potential therapeutic target for DKD.

Chronic kidney disease (CKD) is a clinical syndrome of metabolic disorder caused by progressive kidney impairment for more than 3 months. CKD has become a global public health problem due to its high morbidity and mortality, which is difficult to be cured for most patients. The pathogenesis of CKD is still unclear, which is closely related to glomerulosclerosis, kidney tubular injury and kidney fibrosis. LncRNA is a non-coding RNA with a length of more than 200 nucleotides. It not only participates in intracellular transcriptional regulation, post-transcriptional regulation and epigenetic activities, but also forms a regulatory network together with miRNA and mRNA, to further conduct the reticular regulation in cells. Recently, it has been found that lncRNA participates in pathophysiological mechanism of CKD by regulating glomerulosclerosis, kidney tubular injury and kidney fibrosis. This has also become a new direction of lncRNA in early diagnosis and targeted therapy of CKD.

Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR.

Podocytopathies are a uniquely renal disease syndrome, in which direct or indirect podocyte injury leads to proteinuria or nephrotic syndrome. Of the many factors that contribute to podocytopathies, the abnormal regulation of autophagy, such insufficient or excessive autophagy levels, have been proposed to play a significant role in the occurrence and development of podocytopathies. However, there still has been a lack of systematic and comparative research to elucidate exact role of autophagy in podocytopathies and its current research status. This study aims to utilize bibliometric analysis to clarify the role of autophagy in the pathogenesis of podocytopathies, analyze the research focus in this area, as well as explore the future research trends.

We retrieved original articles and review papers with respect to autophagy in podocytopathies research published between the year 2008 and 2022 from the Web of Science Core Collection (WOSCC). Then, VOSviewer and CiteSpace software were employed to reveal the leading subjects and generate visual maps of countries/regions, organizations, authors, journals, and keyword networks in this field.

A total of 825 publications regarding autophagy in podocytopathies published between 2008 and 2022 were included, with China contributing the most followed by the United States and Japan. Professor Koya Daisuke, Professor He Qiang, and Professor Jin Juan are the most prolific researchers in this field. Oxidative stress, the NLRP3 inflammasome, and therapeutic targets were the knowledge base for the research in this special field. Taken together, this bibliometric analysis helps us reveal the current research hotspots and guide future research directions, which provides a reference for scholars to further investigate the role of autophagy in podocytopathies as well as conduct clinical trial with autophagy regulators in podocytopathies.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in diabetes mellitus. It is also a significant contributor to cardiovascular morbidity and mortality in diabetic patients Thereby, Innovative therapeutic approaches are needed to retard the initiation and advancement of DN. Hyperglycemia can induce apoptosis, a regulated form of cell death, in multiple renal cell types, such as podocytes, mesangial cells, and proximal tubule epithelial cells, ultimately contributing to the pathogenesis of DN. Recent genome-wide investigations have revealed the widespread transcription of the human genome, resulting in the production of numerous regulatory non-protein-coding RNAs (ncRNAs), including microRNAs (miRNAs) and diverse categories of long non-coding RNAs (lncRNAs). They play a critical role in preserving physiological homeostasis, while their dysregulation has been implicated in a broad spectrum of disorders, including DN. Considering the established association between apoptotic processes and the expression of ncRNAs in DN, a thorough understanding of their intricate interplay is essential. Therefore, the current work thoroughly analyzes the intricate interplay among miRNAs, lncRNAs, and circular RNAs in the context of apoptosis within the pathogenesis of DN. Additionally, in the final section, we demonstrated that ncRNA-mediated modulation of apoptosis can be achieved through stem cell-derived exosomes and herbal medicines, presenting potential avenues for the treatment of DN.

Asthenozoospermia (AZS) is one of the most common types of male infertility. Current evidence revealed that type 2 diabetes mellitus (T2DM) is closely associated with declining semen quality, especially for poor sperm motility. This study aimed to uncover the genetic interrelationships and important biomarkers between AZS and T2DM. Transcriptome data regarding AZS and T2DM were downloaded from the Gene Expression Omnibus (GEO) database. We performed GO and pathway analysis, and protein-protein interaction (PPI) network construction for T2DM-related differentially expressed genes (DMRGs). Moreover, we calculated receiver operator characteristic (ROC) curve and conducted external independent validation. Expression of hub DMRGs was assessed for patients using the qPCR method. MiRNA interaction and immune infiltration were subsequently characterized. A total of 554 overlapping DMRGs were identified between the AZS/T2DM and healthy groups. These overlapping DMRG participated in the DNA damage-, energy metabolism-, and immune-related biological pathways. Module function analysis discovered that the top three PPI modules were tightly correlated with DNA damage-related processes. After external validation in other independent datasets, two hub DMRGs (TBC1D12 and SCG5) were obtained. ROC analysis revealed that TBC1D12 and SCG5 had good diagnostic performance (area under the curve > 0.75). Immune infiltration profile showed that the level of T cell co-stimulation and CD8+_T_cells were negatively related to the hub DMRGs expression. Mirna interaction analysis showed 15 significant hub DMRGs-miRNA interactions. The qPCR results showed that expression of TBC1D12 and SCG5 were significantly different between sperm samples from diabetic patients with AZS and controls. The present study revealed molecular signatures and critical pathways between the AZS and T2DM, and identified two hub DMRGs of TBC1D12 and SCG5. The data would provide novel understandings of shared pathogenic mechanisms in T2DM-associated AZS.

Diabetic nephropathy (DN) is a common and serious micro-vascular complication of diabetes and a leading cause of end-stage renal disease globally. This disease primarily affects middle-aged and elderly individuals, especially those with a diabetes history of over 10 years and poor long-term blood glucose control. Small ubiquitin-related modifiers (SUMOs) are a group of reversible post-translational modifications of proteins that are widely expressed in eukaryotes. SUMO proteins intervene in the progression of DN by modulating various signaling cascades, such as Nrf2-mediated oxidative stress, NF-κB, TGF-β, and MAPK pathways. Recent advancements indicate that natural products regulating SUMOylation hold promise as targets for intervening in DN. In a previous article published in 2022, we reviewed the mechanisms by which SUMOylation intervenes in renal fibrosis and presented a summary of some natural products with therapeutic potential. Therefore, this paper will focus on DN. The aim of this review is to elucidate the mechanism of action of SUMOylation in DN and related natural products with therapeutic potential, thereby summarising the targets and candidate natural products for the treatment of DN through the modulation of SUMOylation, such as ginkgolic acid, ginkgolide B, resveratrol, astragaloside IV, etc., and highlighting that natural product-mediated modulation of SUMOylation is a potential therapeutic strategy for the treatment of DN as a potential therapeutic strategy.

Distinguished from cuproptosis and ferroptosis, disulfidptosis has been described as a newly discovered form of non-programmed cell death tightly associated with glucose metabolism. However, the prognostic profile of disulfidptosis-related lncRNAs (DRLRs) in ovarian cancer (OC) and their biological mechanisms need to be further elucidated.

First, we downloaded the profiles of RNA transcriptome, clinical information for OC patients from the TCGA database. Generated from Cox regression analysis, prognostic lncRNAs were utilized to identify the risk signature by least absolute shrinkage and selection operator analysis. Then, we explored the intimate correlations between disulfidptosis and lncRNAs. What's more, we performed a series of systemic analyses to assess the robustness of the model and unravel its relationship with the immune microenvironment comprehensively.

We identified two DRLR clusters, in which OC patients with low-risk scores exhibited a favorable prognosis, up-regulated immune cell infiltrations and enhanced sensitivity to immunotherapy. Furthermore, validation of the signature by clinical features and Cox analysis demonstrated remarkable consistency, suggesting the universal applicability of our model. It's worth noting that high-risk patients showed more positive responses to immune checkpoint inhibitors and potential chemotherapeutic drugs.

Our findings provided valuable insights into DRLRs in OC for the first time, which indicated an excellent clinical value in the selection of management strategies, spreading brilliant horizons into individualized therapy.

To analyze the expression of SPAG5 in gastric cancer tissues and its regulatory roles in gastric cancer cell growth.

TCGA analysis, immunohistochemistry, and immunofluorescence staining were used to analyze the expression patterns of SPAG5 and MKi67 in gastric cancer and adjacent tissues. In gastric cancer AGS and MGC803 cells, the effects of lentivirus-mediated SPAG5 knockdown on cell growth and apoptosis were evaluated using Celigo, MTT, clone formation assays and flow cytometry.

Proteinatlas and TCGA database analysis suggested that SPAG5 was highly expressed in gastric cancer, and Kaplan-Meier analysis and GEPIA analysis showed high expressions of SPAG 5 in lung adenocarcinoma, breast cancer, hepatocellular carcinoma, pancreatic carcinoma, cervical cancer and bladder carcinoma. Immunohistochemistry revealed that SPAG5 was highly expressed in gastric cancer tissues (P < 0.001), and immunofluorescence colocalization analysis demonstrated a significant correlation between SPAG5 and MKI67 (R=0.393, P < 0.001). RT-qPCR and Western blotting showed that SPAG5 was highly expressed in MKN74, BGC823, MGC803, SGC7901 and AGS cells. In AGS and MGC803 cells, SPAG5 knockdown significantly inhibited proliferation and promoted apoptosis.

The expressions of SPAG5 and MKi67 are correlated in gastric cancer tissues, and SPAG5 knockdown inhibits the proliferation of gastric cancer cells. SPAG5 is associated with the prognosis of gastric cancer patients and may serve as a promising biomarker for gastric cancer.

Diabetic kidney disease (DKD) is the primary cause of chronic kidney and end-stage renal disease. Glomerular podocyte loss and death are pathological hallmarks of DKD, and programmed cell death (PCD) in podocytes is crucial in DKD progression. PCD involves apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. During DKD, PCD in podocytes is severely impacted and primarily characterized by accelerated podocyte apoptosis and suppressed autophagy. These changes lead to a gradual decrease in podocyte numbers, impairing the glomerular filtration barrier function and accelerating DKD progression. However, research on the interactions between the different types of PCD in podocytes is lacking. This review focuses on the novel roles and mechanisms of PCD in the podocytes of patients with DKD. Additionally, we summarize clinical drugs capable of regulating podocyte PCD, present challenges and prospects faced in developing drugs related to podocyte PCD and suggest that future research should further explore the detailed mechanisms of podocyte PCD and interactions among different types of PCD.

The intricate crosstalk between long noncoding RNAs (lncRNAs) and epigenetic modifications such as chromatin/histone methylation and acetylation offer new perspectives on the pathogenesis and treatment of kidney diseases. lncRNAs, a class of transcripts longer than 200 nucleotides with no protein-coding potential, are now recognized as key regulatory molecules influencing gene expression through diverse mechanisms. They modulate the epigenetic modifications by recruiting or blocking enzymes responsible for adding or removing methyl or acetyl groups, such as DNA, N6-methyladenosine (m6A) and histone methylation and acetylation, subsequently altering chromatin structure and accessibility. In kidney diseases such as acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), glomerulonephritis (GN), and renal cell carcinoma (RCC), aberrant patterns of DNA/RNA/histone methylation and acetylation have been associated with disease onset and progression, revealing a complex interplay with lncRNA dynamics. Recent studies have highlighted how lncRNAs can impact renal pathology by affecting the expression and function of key genes involved in cell cycle control, fibrosis, and inflammatory responses. This review will separately address the roles of lncRNAs and epigenetic modifications in renal diseases, with a particular emphasis on elucidating the bidirectional regulatory effects and underlying mechanisms of lncRNAs in conjunction with DNA/RNA/histone methylation and acetylation, in addition to the potential exacerbating or renoprotective effects in renal pathologies. Understanding the reciprocal relationships between lncRNAs and epigenetic modifications will not only shed light on the molecular underpinnings of renal pathologies but also present new avenues for therapeutic interventions and biomarker development, advancing precision medicine in nephrology.

Diabetic nephropathy (DN) is a serious complication of diabetes that causes glomerular sclerosis and end-stage renal disease, leading to ascending morbidity and mortality in diabetic patients. Excessive accumulation of aberrantly modified proteins or damaged organelles, such as advanced glycation end-products, dysfunctional mitochondria, and inflammasomes is associated with the pathogenesis of DN. As one of the main degradation pathways, autophagy recycles toxic substances to maintain cellular homeostasis and autophagy dysregulation plays a crucial role in DN progression. MicroRNA (miRNA) and long non-coding RNA (lncRNA) are non-coding RNA (ncRNA) molecules that regulate gene expression and have been implicated in both physiological and pathological conditions. Recent studies have revealed that autophagy-regulating miRNA and lncRNA have been involved in pathological processes of DN, including renal cell injury, mitochondrial dysfunction, inflammation, and renal fibrosis. This review summarizes the role of autophagy in DN and emphasizes the modulation of miRNA and lncRNA on autophagy during disease progression, for the development of promising interventions by targeting these ncRNAs in this disease.

Autophagy is a protective mechanism through which cells degrade and recycle proteins and organelles to maintain cellular homeostasis and integrity. An accumulating body of evidence underscores the significant impact of dysregulated autophagy on podocyte injury in chronic kidney disease (CKD). In this review, we provide a comprehensive overview of the diverse types of autophagy and their regulation in cellular homeostasis, with a specific emphasis on podocytes. Furthermore, we discuss recent findings that focus on the functional role of different types of autophagy during podocyte injury in chronic kidney disease. The intricate interplay between different types of autophagy and podocyte health requires further research, which is critical for understanding the pathogenesis of CKD and developing targeted therapeutic interventions.

IgA nephropathy (IgAN) is a prevalent worldwide glomerular disease with a complex pathophysiology that has significant economic implications. Despite the lack of successful research, this study aims to discover the potential competing endogenous RNA (ceRNA) network of autophagy-associated genes in IgAN and examine their correlation with immune cell infiltration.

Autophagy-related hub genes were discovered by assessing the GSE116626 dataset and constructing a protein-protein interaction network. Nephroseq v5 analysis engine was used to analyze correlations between hub genes and proteinuria, glomerular filtration rate (GFR), and serum creatinine levels. Then, a ceRNA network construction and the CIBERSORT tool for immune cell infiltration analysis were also performed. Additionally, the differentially expressed autophagy-related genes were used to predict potential targeted medications for IgAN.

Overall, 1,396 differentially expressed genes were identified in IgAN along with 25 autophagy-related differentially expressed messenger RNAs. Enrichment analysis revealed significant involvement of autophagy and apoptosis in biological processes. Next, we evaluated the top hub nodes based on their highest degrees. The ability of IgAN discrimination was confirmed in the GSE35487 and GSE37460 datasets by validating the five hub genes: SIRT1, FOS, CCL2, CDKN1A, and MYC. In the Nephroseq v5 analysis engine, the clinical correlation of the five hub genes was confirmed. Furthermore, the ceRNA network identified 18 circular RNAs and 2 microRNAs associated with hub autophagy-related genes in IgAN. Our investigation identified hsa-miR-32-3p and hsa-let-7i-5p as having elevated expression levels and substantial diagnostic value. Finally, four distinctively infiltrated immune cells were found to be associated with the hub autophagy-related genes, and 67 drugs were identified as potential therapeutic options for IgAN.

This study sheds light on a novel ceRNA regulatory network mechanism associated with autophagy in IgAN development.

Autophagy, as a regulator of cell survival, plays an important role in atherosclerosis (AS). Sperm associated antigen 5 (SPAG5) is closely associated with the classical autophagy pathway, PI3K/Akt/mTOR signaling pathway. This work attempted to investigate whether SPAG5 can affect AS development by regulating autophagy.

Human umbilical vein endothelial cells (HUVECs) were treated with oxidized-low density lipoprotein (ox-LDL) to induce cell damage. ApoE-/- mice were fed a Western diet to establish an AS mouse model. Haematoxylin and eosin (H&E) staining and Oil Red O staining evaluated the pathological changes and in lipid deposition in aortic tissues. CCK-8 and flow cytometry detected cell proliferation and apoptosis. Immunohistochemistry, Enzyme linked immunosorbent assay, qRT-PCR and western blotting assessed the levels of mRNA and proteins.

Ox-LDL treatment elevated SPAG5 expression and the expression of autophagy-related proteins, LC3-I, LC3-II, Beclin-1, and p62, in HUVECs. GFP-LC3 dots were increased in ox-LDL-treated HUVECs and LPS-treated HUVECs. SPAG5 knockdown reversed both ox-LDL and LPS treatment-mediated inhibition of cell proliferation and promotion of apoptosis in HUVECs. SPAG5 silencing further elevated autophagy and repressed the expression of PI3K, p-Akt/Akt, and p-mTOR/mTOR in ox-LDL-treated HUVECs. 3-MA (autophagy inhibitor) treatment reversed SPAG5 silencing-mediated increase of cell proliferation and decrease of apoptosis in ox-LDL-treated HUVECs. In vivo, SPAG5 knockdown reduced atherosclerotic plaques in AS mice through activating autophagy and inhibiting PI3K/Akt/mTOR signaling pathway.

This work demonstrated that SPAG5 knockdown alleviated AS development through activating autophagy. Thus, SPAG5 may be a potential target for AS therapy.

Colorectal cancer has a low 5-year survival rate and high mortality. Human β-defensin-1 (hBD-1) may play an integral function in the innate immune system, contributing to the recognition and destruction of cancer cells. Long non-coding RNAs (lncRNAs) are involved in the process of cell differentiation and growth.

To investigate the effect of hBD-1 on the mammalian target of rapamycin (mTOR) pathway and autophagy in human colon cancer SW620 cells.

CCK8 assay was utilized for the detection of cell proliferation and determination of the optimal drug concentration. Colony formation assay was employed to assess the effect of hBD-1 on SW620 cell proliferation. Bioinformatics was used to screen potentially biologically significant lncRNAs related to the mTOR pathway. Additionally, p-mTOR (Ser2448), Beclin1, and LC3II/I expression levels in SW620 cells were assessed through Western blot analysis.

hBD-1 inhibited the proliferative ability of SW620 cells, as evidenced by the reduction in the colony formation capacity of SW620 cells upon exposure to hBD-1. hBD-1 decreased the expression of p-mTOR (Ser2448) protein and increased the expression of Beclin1 and LC3II/I protein. Furthermore, bioinformatics analysis identified seven lncRNAs (2 upregulated and 5 downregulated) related to the mTOR pathway. The lncRNA TCONS_00014506 was ultimately selected. Following the inhibition of the lncRNA TCONS_00014506, exposure to hBD-1 inhibited p-mTOR (Ser2448) and promoted Beclin1 and LC3II/I protein expression.

hBD-1 inhibits the mTOR pathway and promotes autophagy by upregulating the expression of the lncRNA TCONS_00014506 in SW620 cells.

Podocyte apoptosis exerts a crucial role in the pathogenesis of DN. Recently, long noncoding RNAs (lncRNAs) have been gradually identified to be functional in a variety of different mechanisms associated with podocyte apoptosis. This study aimed to investigate whether lncRNA Glis2 could regulate podocyte apoptosis in DN and uncover the underlying mechanism. The apoptosis rate was detected by flow cytometry. Mitochondrial membrane potential (ΔΨM) was measured using JC-1 staining. Mitochondrial morphology was detected by MitoTracker Deep Red staining. Then, the histopathological and ultrastructure changes of renal tissues in diabetic mice were observed using periodic acid-Schiff (PAS) staining and transmission electron microscopy. We found that lncRNA Glis2 was significantly downregulated in high-glucose cultured podocytes and renal tissues of db/db mice. LncRNA Glis2 overexpression was found to alleviate podocyte mitochondrial dysfunction and apoptosis. The direct interaction between lncRNA Glis2 and miR-328-5p was confirmed by dual luciferase reporter assay. Furthermore, lncRNA Glis2 overexpression alleviated podocyte apoptosis in diabetic mice. Taken together, this study demonstrated that lncRNA Glis2, acting as a competing endogenous RNA (ceRNA) of miRNA-328-5p, regulated Sirt1-mediated mitochondrial dysfunction and podocyte apoptosis in DN.

A growing amount of epidemiological evidence proposes diabetes mellitus (DM) to be an independent risk factor for osteoarthritis (OA). Sirtuin 3 (SIRT3), which is mainly located in mitochondria, belongs to the family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases and is involved in the physiological and pathological processes of cell regulation. The aim of this study was to investigate the effects of SIRT3 on diabetic OA and underlying mechanisms in the prevention of type 2 DM (T2DM)-induced articular cartilage damage. High-fat and high-sugar diets combined with streptozotocin (STZ) injection were used for establishing an experimental T2DM rat model. The destabilization of medial meniscus (DMM) surgery was applied to induce the rat OA model. Primary rat chondrocytes were cultivated with a concentration of gradient glucose. Treatment with intra-articular injection of SIRT3 overexpression lentivirus was achieved in vivo, and intervention with SIRT3 knockdown was performed using siRNA transfection in vitro. High glucose content was found to activate inflammatory response, facilitate apoptosis, downregulate autophagy, and exacerbate mitochondrial dysfunction in a dose-dependent manner in rat chondrocytes, which can be deteriorated by SIRT3 knockdown. In addition, articular cartilage damage was found to be more severe in T2DM-OA rats than in DMM-induced OA rats, which can be mitigated by the intra-articular injection of SIRT3 overexpression lentivirus. Targeting SIRT3 is a potential therapeutic strategy for the alleviation of diabetic OA.

Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetes and can potentially develop into end-stage renal disease. Its pathogenesis is complex and not fully understood. Podocytes, glomerular endothelial cells (GECs), glomerular mesangial cells (GMCs) and renal tubular epithelial cells (TECs) play important roles in the normal function of glomerulus and renal tubules, and their injury is involved in the progression of DN. Although our understanding of the mechanisms leading to DN has substantially improved, we still need to find more effective therapeutic targets. Autophagy, pyroptosis and ferroptosis are programmed cell death processes that are associated with inflammation and are closely related to a variety of diseases. Recently, a growing number of studies have reported that autophagy, pyroptosis and ferroptosis regulate the function of podocytes, GECs, GMCs and TECs. This review highlights the contributions of autophagy, pyroptosis, and ferroptosis to DN injury in these cells, offering potential therapeutic targets for DN treatment.

Podocyte apoptosis plays a vital role in proteinuria pathogenesis in diabetic nephropathy (DN). The regulatory relationship between long noncoding RNAs (lncRNAs) and podocyte apoptosis has recently become another research hot spot in the DN field.

To investigate whether lncRNA protein-disulfide isomerase-associated 3 (Pdia3) could regulate podocyte apoptosis through miR-139-3p and revealed the underlying mechanism.

Using normal glucose or high glucose (HG)-cultured podocytes, the cellular functions and exact mechanisms underlying the regulatory effects of lncRNA Pdia3 on podocyte apoptosis and endoplasmic reticulum stress (ERS) were explored. LncRNA Pdia3 and miR-139-3p expression were measured through quantitative real-time polymerase chain reaction. Relative cell viability was detected through the cell counting kit-8 colorimetric assay. The podocyte apoptosis rate in each group was measured through flow cytometry. The interaction between lncRNA Pdia3 and miR-139-3p was examined through the dual luciferase reporter assay. Finally, western blotting was performed to detect the effect of lncRNA Pdia3 on podocyte apoptosis and ERS via miR-139-3p.

The expression of lncRNA Pdia3 was significantly downregulated in HG-cultured podocytes. Next, lncRNA Pdia3 was involved in HG-induced podocyte apoptosis. Furthermore, the dual luciferase reporter assay confirmed the direct interaction between lncRNA Pdia3 and miR-139-3p. LncRNA Pdia3 overexpression attenuated podocyte apoptosis and ERS through miR-139-3p in HG-cultured podocytes.

Taken together, this study demonstrated that lncRNA Pdia3 overexpression could attenuate HG-induced podocyte apoptosis and ERS by acting as a competing endogenous RNA of miR-139-3p, which might provide a potential therapeutic target for DN.

Ubiquitin-specific proteases (USPs), as one of the deubiquitinating enzymes (DUBs) families, regulate the fate of proteins and signaling pathway transduction by removing ubiquitin chains from the target proteins. USPs are essential for the modulation of a variety of physiological processes, such as DNA repair, cell metabolism and differentiation, epigenetic modulations as well as protein stability. Recently, extensive research has demonstrated that USPs exert a significant impact on innate and adaptive immune reactions, metabolic syndromes, inflammatory disorders, and infection via post-translational modification processes. This review summarizes the important roles of the USPs in the onset and progression of inflammatory diseases, including periodontitis, pneumonia, atherosclerosis, inflammatory bowel disease, sepsis, hepatitis, diabetes, and obesity. Moreover, we highlight a comprehensive overview of the pathogenesis of USPs in these inflammatory diseases as well as post-translational modifications in the inflammatory responses and pave the way for future prospect of targeted therapies in these inflammatory diseases.

Diabetic retinopathy (DR) is an ocular disease caused by diabetes and may lead to vision impairment and even blindness. Oxidative stress and inflammation are two key pathogenic factors of DR. Recently, regulatory roles of different microRNAs (miRNAs) in DR have been widely verified. miR-26a-5p has been confirmed to be a potential biomarker of DR. Nevertheless, the specific functions of miR-26a-5p in DR are still unclear.

Primary cultured mouse retinal Müller cells in exposure to high glucose (HG) were used to establish an in vitro DR model. Müller cells were identified via morphology observation under phase contrast microscope and fluorescence staining for glutamine synthetase. The in vivo animal models for DR were constructed using streptozotocin-induced diabetic C57BL/6 mice. Western blotting was performed to quantify cytochrome c protein level in the cytoplasm and mitochondria of Müller cells and to measure protein levels of glial fibrillary acidic protein (GFAP), ubiquitin-specific peptidase 14 (USP14), as well as factors associated with NF-κB signaling (p-IκBα, IκBα, p-p65, and p65) in Müller cells or murine retinal tissues. ROS production was detected by CM-H2DCFDA staining, and the concentration of oxidative stress markers (MDA, SOD, and CAT) was estimated by using corresponding commercial kits. Quantification of mRNA expression was conducted by RT-qPCR analysis. The concentration of proinflammatory factors (TNF-α, IL-1β, and IL-6) was evaluated by ELISA. Hematoxylin-eosin staining for murine retinal tissues was performed for histopathological analysis. Immunofluorescence staining was conducted to determine NF-κB p65 nuclear translocation in Müller cells. Furthermore, the interaction between miR-26a-5p and USP14 was verified via the luciferase reporter assays.

HG stimulation contributed to Müller cell dysfunction by inducing inflammation, oxidative injury, and mitochondrial damage to Müller cells. miR-26a-5p was downregulated in Müller cells under HG condition, and overexpression of miR-26a-5p relieved HG-induced Müller cell dysfunction. Moreover, miR-26a-5p targeted USP14 and inversely regulated USP14 expression. Additionally, HG-evoked activation of NF-κB signaling was suppressed by USP14 knockdown or miR-26a-5p upregulation. Rescue assays showed that the protective impact of miR-26a-5p upregulation against HG-induced Müller cell dysfunction was reversed by USP14 overexpression. Furthermore, USP14 upregulation and activation of NF-κB signaling in the retinas of DR mice were detected in animal experiments. Injection with miR-26a-5p agomir improved retinal histopathological injury and weakened the concentration of proinflammatory cytokines and oxidative stress markers in the retinas of DR mice.

miR-26a-5p inhibits oxidative stress and inflammation in DR progression by targeting USP14 and inactivating the NF-κB signaling pathway.

The development of diabetic nephropathy (DN) could be promoted by the occurrence of tubulointerstitial fibrosis (TIF), which has a close relationship with mitochondrial dysfunction of renal tubular epithelial cells (RTECs). As a key regulator of metabolic homeostasis, Yin Yang 1 (YY1) plays an important role not only in regulating the fibrosis process but also in maintaining the mitochondrial function of pancreatic β-cells. However, it was not clear whether YY1 participated in maintaining mitochondrial function of RTECs in early DN-associated TIF. In this study, we dynamically detected mitochondrial functions and protein expression of YY1 in db/db mice and high glucose (HG)-cultured HK-2 cells. Our results showed that comparing with the occurrence of TIF, the emergence of mitochondrial dysfunction of RTECs was an earlier even, besides the up-regulated and nuclear translocated YY1. Correlation analysis showed YY1 expressions were negatively associated with PGC-1α in vitro and in vivo. Further mechanism research demonstrated the formation of mTOR-YY1 heterodimer induced by HG up-regulated YY1, the nuclear translocation of which inactivated PGC-1α by binding to the PGC-1α promoter. Overexpression of YY1 induced mitochondrial dysfunctions in normal glucose-cultured HK-2 cells and 8-weeks-old db/m mice. While, dysfunctional mitochondria induced by HG could be improved by knockdown of YY1. Finally, downregulation of YY1 could retard the progression of TIF by preventing mitochondrial functions, resulting in the improvement of epithelial-mesenchymal transition (EMT) in early DN. These findings suggested that YY1 was a novel regulator of mitochondrial function of RTECs and contributed to the occurrence of early DN-associated TIF.

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, posing significant challenges in terms of early prevention, clinical diagnosis, and treatment. Consequently, it has emerged as a major contributor to end-stage renal disease. The glomerular filtration barrier, composed of podocytes, endothelial cells, and the glomerular basement membrane, plays a vital role in maintaining renal function. Disruptions in podocyte function, including hypertrophy, shedding, reduced density, and apoptosis, can impair the integrity of the glomerular filtration barrier, resulting in elevated proteinuria, abnormal glomerular filtration rate, and increased creatinine levels. Hence, recent research has increasingly focused on the role of podocyte injury in DN, with a growing emphasis on exploring therapeutic interventions targeting podocyte injury. Studies have revealed that factors such as lipotoxicity, hemodynamic abnormalities, oxidative stress, mitochondrial dysfunction, and impaired autophagy can contribute to podocyte injury. This review aims to summarize the underlying mechanisms of podocyte injury in DN and provide an overview of the current research status regarding experimental drugs targeting podocyte injury in DN. The findings presented herein may offer potential therapeutic targets and strategies for the management of DN associated with podocyte injury.

Chronic cerebral hypoperfusion (CCH) can cause a series of pathophysiological processes, including neuronal autophagy and apoptosis. VEGF-A has been reported to affect angiogenesis and neurogenesis in many CNS diseases. However, its effects on neuronal autophagy and apoptosis, as well as the underlying mechanisms in CCH remain unclear.

To address these issues, the CCH model was established by permanent bilateral common carotid artery occlusion (2VO). Rats were sacrificed at different stages of CCH. Hippocampal morphological and ultrastructural changes were detected using HE staining and electron microscopy. The immunoreactivities of microtubule-associated protein 1 light chain 3 (LC3) and phospho-cAMP response element binding protein (p-CREB) were examined by immunofluorescence staining. The neuronal apoptosis was detected via TUNEL staining. The levels of LC3-II, Beclin-1, Akt, p-Akt, CREB, p-CREB, Caspase-3, and Bad were accessed by Western blotting. Furthermore, mouse hippocampal HT22 neurons received the oxygen and glucose deprivation (OGD) treatment, VEGF-A treatment, and GSK690693 (an Akt inhibitor) treatment, respectively.

LC3-II protein started to increase at 3 days of CCH, peaked at 4 weeks of CCH, then decreased. CCH increased the levels of LC3-II, Caspase-3, and Bad, and decreased the levels of p-Akt, CREB, and p-CREB, which were reversed by VEGF-A treatment. VEGF-A also improved CCH-induced neuronal ultrastructural injuries and apoptosis in the hippocampus in vitro. In HT22, the anti-apoptosis and pro-phosphorylation of VEGF-A were reversed by GSK690693.

Present results provide a novel neuroprotective effect of VEGF-A in CCH that is related to the inhibition of neuronal autophagy and activation of the Akt/CREB signaling, suggesting a potential therapeutic strategy for ischemic brain damage.

Podocyte apoptosis is one of the important pathological mechanisms of diabetic kidney disease (DKD). Acteoside (Act), a major active component of Rehmannia glutinosa leaves total glycoside, has a strong renoprotective action. Our study aims to demonstrate Act's renoprotective actions in db/db mice.

We adopted C57BLKS/J db/db mice as DKD animal models. After 8 weeks of Act administration, the 24-hour urine albumin, renal function index, and blood lipid levels were quantified using matching kits. Renal pathology was evaluated by HE and PAS staining. The podocyte damage and apoptosis-related signaling pathway were observed by using immunohistochemistry, western blot, and TUNEL staining.

The albuminuria of db/db mice was reduced from 391 ug/24 h to 152 ug/24 h, and renal pathology changes were alleviated after Act administration. The western blot and immunohistochemistry showed that Act treatment upregulated the synaptopodin and podocin expression compared with db/db mice, while the TUNEL staining indicated podocyte apoptosis was inhibited. The B-cell lymphoma-2 (Bcl-2) level was upregulated in the Act group, but cleaved caspase-3 and Bcl-2 associated X protein (Bax) expression declined, while the protein kinase B/glycogen synthase kinase-3β (AKT/GSK-3β) signaling pathway was repressed.

By inhibiting the AKT/GSK-3β signaling pathway, Act protected podocytes from apoptosis, decreasing the urine albumin of db/db mice and delaying the course of DKD.

Minimal change disease (MCD) is the common type of nephrotic syndrome (NS) in children. Currently, there is an urgent need to explore new treatments because of the significant side effects of long-term use of glucocorticoids and immunosuppressive drugs and the failure to reduce proteinuria in some patients. Angiopoietin-like protein 3 (Angptl3) is an essential target of NS, and anti-ANGPTL3-FLD monoclonal antibody (mAb) significantly reduces proteinuria in mice with adriamycin nephropathy (AN). However, some proteinuria is persistent. Minnelide, a water-soluble prodrug of triptolide, has been used for the treatment of glomerular disease. Therefore, the present study aimed to investigate whether minnelide combined with mAb could further protect mice with AN and the underlying mechanisms. 8-week-old C57BL/6 female mice were injected with 25 mg/kg of Adriamycin (ADR) by tail vein to establish the AN model. A dose of 200 μg/kg of minnelide or 20 mg/kg of mAb was administered intraperitoneally for the treatment. In vitro, the podocytes were treated with 0.4 μg/mL of ADR for 24 h to induce podocyte injury, and pretreatment with 10 ng/mL of triptolide for 30 min or 100 ng/mL of mAb for 1 h before ADR exposure was used to treat. The results showed that minnelide combined with mAb almost completely ameliorates proteinuria and restores the ultrastructure of the podocytes in mice with AN. In addition, minnelide combined with mAb restores the distribution of Nephrin, Podocin, and CD2AP and reduces the level of inflammatory factors in mice with AN. Mechanistically, minnelide combined with mAb could further alleviate apoptosis and promote autophagy in mice with AN by inhibiting the mTOR signaling pathway. In vitro, triptolide combined with mAb increases the expression of Nephrin, Podocin, and CD2AP, alleviates apoptosis, and promotes autophagy. Overall, minnelide combined with mAb completely protects the mice with AN by promoting autophagy and inhibiting apoptosis.

Autophagy is a complex process of lysosomal-dependent degradation of unwanted cellular material. In response to endogenous or exogenous stimuli, autophagy is induced and regulated by two kinases: the AMP activated kinase and the mammalian target of rapamycin (mTOR). Cells activated by Unc-51-like kinase 1 form a double membrane complex that sequesters the cargo (phagophore) and elongates producing spherical vesicles (autophagosomes). These reach and fuse with lysosomes, which degrade the cargo (autolysosomes). The resulting macromolecules are released back and recycled in the cytosol for reuse. In the podocyte, autophagy is a homeostatic mechanism that contributes to the formation and preservation of the morphological and functional integrity of actin cytoskeleton. Podocytes, fenestrated endothelial cells and glomerular basement membrane compose the glomerular filtration barrier. Podocyte damage may cause dysfunction of the glomerular barrier, proteinuria and glomerulosclerosis in different glomerular diseases and particularly in so-called podocytopathies, namely minimal change disease and focal segmental glomerulosclerosis. Several drugs and molecules may activate autophagic function in murine models. Among them, aldosterone inhibitors, mineralocorticoid inhibitors and vitamin D3 were proven to protect podocyte from injury and reduce proteinuria in clinical studies. However, no clinical trial with autophagy regulators in podocytopathies has been conducted. Caution is needed with other autophagy activators, such as mTOR inhibitors and metformin, because of potential adverse events.

Bone marrow-derived mesenchymal stem cells (MSCs) show podocyte-protective effects in chronic kidney disease. Calycosin (CA), a phytoestrogen, is isolated from Astragalus membranaceus with a kidney-tonifying effect. CA preconditioning enhances the protective effect of MSCs against renal fibrosis in mice with unilateral ureteral occlusion. However, the protective effect and underlying mechanism of CA-pretreated MSCs (MSCsCA) on podocytes in adriamycin (ADR)-induced focal segmental glomerulosclerosis (FSGS) mice remain unclear.

To investigate whether CA enhances the role of MSCs in protecting against podocyte injury induced by ADR and the possible mechanism involved.

ADR was used to induce FSGS in mice, and MSCs, CA, or MSCsCA were administered to mice. Their protective effect and possible mechanism of action on podocytes were observed by Western blot, immunohistochemistry, immunofluorescence, and real-time polymerase chain reaction. In vitro, ADR was used to stimulate mouse podocytes (MPC5) to induce injury, and the supernatants from MSC-, CA-, or MSCsCA-treated cells were collected to observe their protective effects on podocytes. Subsequently, the apoptosis of podocytes was detected in vivo and in vitro by Western blot, TUNEL assay, and immunofluorescence. Overexpression of Smad3, which is involved in apoptosis, was then induced to evaluate whether the MSCsCA-mediated podocyte protective effect is associated with Smad3 inhibition in MPC5 cells.

CA-pretreated MSCs enhanced the protective effect of MSCs against podocyte injury and the ability to inhibit podocyte apoptosis in ADR-induced FSGS mice and MPC5 cells. Expression of p-Smad3 was upregulated in mice with ADR-induced FSGS and MPC5 cells, which was reversed by MSCCA treatment more significantly than by MSCs or CA alone. When Smad3 was overexpressed in MPC5 cells, MSCsCA could not fulfill their potential to inhibit podocyte apoptosis.

MSCsCA enhance the protection of MSCs against ADR-induced podocyte apoptosis. The underlying mechanism may be related to MSCsCA-targeted inhibition of p-Smad3 in podocytes.

Mechanistic target of rapamycin (mTOR), a highly conserved serine/threonine kinase, is involved in cellular metabolism, protein synthesis, and cell death. Programmed cell death (PCD) assists in eliminating aging, damaged, or neoplastic cells, and is indispensable for sustaining normal growth, fighting pathogenic microorganisms, and maintaining body homeostasis. mTOR has crucial functions in the intricate signaling pathway network of multiple forms of PCD. mTOR can inhibit autophagy, which is part of PCD regulation. Cell survival is affected by mTOR through autophagy to control reactive oxygen species production and the degradation of pertinent proteins. Additionally, mTOR can regulate PCD in an autophagy-independent manner by affecting the expression levels of related genes and phosphorylating proteins. Therefore, mTOR acts through both autophagy-dependent and -independent pathways to regulate PCD. It is conceivable that mTOR exerts bidirectional regulation of PCD, such as ferroptosis, according to the complexity of signaling pathway networks, but the underlying mechanisms have not been fully explained. This review summarizes the recent advances in understanding mTOR-mediated regulatory mechanisms in PCD. Rigorous investigations into PCD-related signaling pathways have provided prospective therapeutic targets that may be clinically beneficial for treating various diseases.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that results in severe pain and stiffness in the joints. The causes and pathophysiology of AS are still largely unknown. The lncRNA H19 plays key roles in the pathogenesis of AS by mediating inflammatory progression by acting in the axis of IL-17A/IL-23. The aims of this study were determining the role of lncRNA H19 in AS and assessing its clinical correlation. A case-control study was conducted and qRT-PCR was utilized to measure H19 expression. Comparing AS cases to healthy controls, it was found that H19 expression was significantly upregulated. For AS prediction, H19 demonstrated a 81.1% sensitivity, 100% specificity, and 90.6% diagnostic accuracy at a lncRNA H19 expression value of 1.41. lncRNA H19 had a significantly positive correlation with AS activity, MRI results, and inflammatory markers. lncRNA H19 seemed to be an independent predictor of AS (adjusted OR of 211 (95% CI: 4.7-939; p = 0.025)). After 3 months of clinical follow-up, seventeen patients (32.1%) showed minimal clinical improvement and fifteen patients (28.3%) showed major improvement. AS activity scores were significantly decreased in patients with high H19 expression. A significantly elevated lncRNA H19 expression was observed in AS cases compared with that in healthy controls. These results suggest that upregulation of lncRNA H19 expression may be involved in the pathogenesis of AS. The expression of the lncRNA H19 is related to the duration and activity of the disease. LncRNA H19 expression seems to be an independent predictor of AS.

Diabetic nephropathy is one of the leading causes of end-stage renal disease worldwide. In our study we found that Adenosine triphosphate (ATP) content was significantly increased in the urine of diabetic mice. We examined the expression of all purinergic receptors in the renal cortex and found that only purinergic P2X7 receptor (P2X7R) expression was significantly increased in the renal cortex of wild-type diabetic mice and that the P2X7R protein partially co-localized with podocytes. Compared with P2X7R(-/-) non-diabetic mice, P2X7R(-/-) diabetic mice showed stable expression of the podocyte marker protein podocin in the renal cortex. The renal expression of microtubule associated protein 1A/1B light chain 3 (LC-3II) in wild-type diabetic mice was significantly lower than in wild-type controls, whereas the expression of LC-3II in the kidneys of P2X7R(-/-) diabetic mice was not significantly different from that of P2X7R(-/-) non-diabetic mice. In vitro, high glucose induced an increase in p-Akt/Akt, p-mTOR/mTOR and p62 protein expression along with a decrease in LC-3II levels in podocytes, whereas after transfection with P2X7R siRNA, Phosphorylated serine/threonine kinase (p-Akt)/Akt, Phosphorylated mechanistic target of rapamycin (p-mTOR)/mTOR, and p62 expression were restored and LC-3II expression was increased. In addition, LC-3II expression was also restored after inhibition of Akt and mTOR signaling with MK2206 and rapamycin, respectively. Our results suggest that P2X7R expression is increased in podocytes in diabetes, and that P2X7R is involved in the inhibition of podocyte autophagy by high glucose, at least in part through the Akt-mTOR pathway, thereby exacerbating podocyte damage and promoting the onset of diabetic nephropathy. Targeting P2X7R may be a potential treatment for diabetic nephropathy.

Chromatin remodeling is the one of the main epigenetic mechanisms of gene expression regulation both in normal cells and in pathological conditions. In recent years, a growing number of investigations have confirmed that epigenetic regulators are tightly connected and form a comprehensive network of regulatory pathways and feedback loops. Genes encoding protein subunits of chromatin remodeling complexes are often mutated and change their expression in diseases, as well as non-coding RNAs (ncRNAs). Moreover, different mechanisms of their mutual regulation have already been described. Further understanding of these processes may help apply their clinical potential for establishment of the diagnosis, prognosis, and treatment of the diseases. The therapeutic targeting of the chromatin structure has many limitations because of the complexity of its regulation, with the involvement of a large number of genes, proteins, non-coding transcripts, and other intermediary molecules. However, several successful strategies have been proposed to target subunits of chromatin remodeling complexes and genes encoding them, as well as the ncRNAs that regulate the operation of these complexes and direct them to the target gene regions. In our review, we focus on chromatin remodeling complexes and ncRNAs, their mutual regulation, role in cellular processes and potential clinical application.

Diabetic nephropathy (DN), the leading cause of end-stage renal disease, is the most significant microvascular complication of diabetes and poses a severe public health concern due to a lack of effective clinical treatments. Autophagy is a lysosomal process that degrades damaged proteins and organelles to preserve cellular homeostasis. Emerging studies have shown that disorder in autophagy results in the accumulation of damaged proteins and organelles in diabetic renal cells and promotes the development of DN. Autophagy is regulated by nutrient-sensing pathways including AMPK, mTOR, and Sirt1, and several intracellular stress signaling pathways such as oxidative stress and endoplasmic reticulum stress. An abnormal nutritional status and excess cellular stresses caused by diabetes-related metabolic disorders disturb the autophagic flux, leading to cellular dysfunction and DN. Here, we summarized the role of autophagy in DN focusing on signaling pathways to modulate autophagy and therapeutic interferences of autophagy in DN.

Ovarian cancer and renal cancer are malignant tumors; however, the relationship between TTK Protein Kinase (TTK), AKT-mTOR pathway and ovarian cancer, renal cancer remains unclear.

Download GSE36668 and GSE69428 from Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed. Created protein-protein interaction (PPI) network. Used Gene Ontology analysis (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional enrichment analysis. Gene Set Enrichment Analysis (GSEA) analysis and survival analysis were performed. Created animal model for western blot analysis. Gene Expression Profiling Interactive Analysis (GEPIA) was performed to explore the role of TTK on the overall survival of renal cancer.

GO showed that DEGs were enriched in anion and small molecule binding, and DNA methylation. KEGG analysis presented that they mostly enriched in cholesterol metabolism, type 1 diabetes, sphingolipid metabolism, ABC transporters, etc., TTK, mTOR, p-mTOR, AKT, p-AKT, 4EBP1, p-4EBP1 and Bcl-2 are highly expressed in ovarian cancer, Bax, Caspase3 are lowly expressed in ovarian cancer, cell apoptosis is inhibited, leading to deterioration of ovarian cancer. Furthermore, the TTK was not only the hub biomarker of ovarian cancer, but also one significant hub gene of renal cancer, and its expression was up-regulated in the renal cancer. Compared with the renal cancer patients with low expression of TTK, the patients with high expression of TTK have the poor overall survival (P = 0.0021).

TTK inhibits apoptosis through AKT-mTOR pathway, worsening ovarian cancer. And TTK was also one significant hub biomarker of renal cancer.

Ubiquitination and deubiquitination are reversible processes that modify the characteristics of target proteins, including stability, intracellular localization, and enzymatic activity. Ubiquitin-specific proteases (USPs) constitute the largest deubiquitinating enzyme family. To date, accumulating evidence indicates that several USPs positively and negatively affect metabolic diseases. USP22 in pancreatic β-cells, USP2 in adipose tissue macrophages, USP9X, 20, and 33 in myocytes, USP4, 7, 10, and 18 in hepatocytes, and USP2 in hypothalamus improve hyperglycemia, whereas USP19 in adipocytes, USP21 in myocytes, and USP2, 14, and 20 in hepatocytes promote hyperglycemia. In contrast, USP1, 5, 9X, 14, 15, 22, 36, and 48 modulate the progression of diabetic nephropathy, neuropathy, and/or retinopathy. USP4, 10, and 18 in hepatocytes ameliorates non-alcoholic fatty liver disease (NAFLD), while hepatic USP2, 11, 14, 19, and 20 exacerbate it. The roles of USP7 and 22 in hepatic disorders are controversial. USP9X, 14, 17, and 20 in vascular cells are postulated to be determinants of atherosclerosis. Moreover, mutations in the Usp8 and Usp48 loci in pituitary tumors cause Cushing syndrome. This review summarizes the current knowledge about the modulatory roles of USPs in energy metabolic disorders.

Vascular calcification and aging often increase morbidity and mortality in patients with diabetes mellitus (DM); however, the underlying mechanisms are still unknown. In the present study, we found that Bcl-2 modifying factor (BMF) and BMF antisense RNA 1 (BMF-AS1) were significantly increased in high glucose-induced calcified and senescent vascular smooth muscle cells (VSMCs) as well as artery tissues from diabetic mice. Inhibition of BMF-AS1 and BMF reduced the calcification and senescence of VSMCs, whereas overexpression of BMF-AS1 and BMF generates the opposite results. Mechanistic analysis showed that BMF-AS1 interacted with BMF directly and up-regulated BMF at both mRNA and protein levels, but BMF did not affect the expression of BMF-AS1. Moreover, knocking down BMF-AS1 and BMF suppressed the calcification and senescence of VSMCs, and BMF knockout (BMF^-/-) diabetic mice presented less vascular calcification and aging compared with wild type diabetic mice. In addition, higher coronary artery calcification scores (CACs) and increased plasma BMF concentration were found in patients with DM, and there was a positive correlation between CACs and plasma BMF concentration. Thus, BMF-AS1/BMF plays a key role in promoting high glucose-induced vascular calcification and aging both in vitro and in vivo. BMF-AS1 and BMF represent potential therapeutic targets in diabetic vascular calcification and aging.