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Lung adenocarcinoma (LUAD) is the most prevalent histological subtype of non-small cell lung cancer (NSCLC) and is characterized by high mortality and limited therapeutic efficacy in advanced stages. AVEN, an apoptosis inhibitor that interacts with Bcl-xL and Apaf-1 to suppress caspase activation, has been implicated in tumour progression and drug resistance in various cancers. However, its role in LUAD remains unclear. In this study, the prognostic importance, immune microenvironment association, and regulatory mechanisms of AVEN in LUAD were comprehensively investigated using bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and experimental validation. Analysis of the TCGA and GEO datasets revealed that AVEN expression was significantly upregulated in LUAD tissues compared with normal tissues and that high AVEN expression correlated with advanced T/N stage and pathological stage and was associated with poor overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). Multivariate Cox regression identified AVEN expression as an independent prognostic factor, and a nomogram incorporating AVEN expression demonstrated high predictive accuracy for 1-, 3-, and 5-year OS. Functional enrichment analysis linked AVEN to keratinocyte differentiation, spliceosome activity, and cell cycle pathways, whereas the results of scRNA-seq highlighted its predominant expression in malignant epithelial cell subtypes (tS2), which is associated with aggressive proliferation and immune evasion. AVEN expression was positively correlated with Th2, NK CD56dim, and Tgd cell infiltration but negatively associated with TFH, eosinophil, and mast cell infiltration, suggesting its role in modulating the tumour immune microenvironment. Detection of clinical samples verified the high expression of AVEN in LUAD. In vitro, AVEN knockdown in A549 cells suppressed proliferation, migration, and invasion while promoting apoptosis. Furthermore, bioinformatics prediction and validation revealed that hsa-miR-30d-5p was an upstream regulator of AVEN, with its low expression in LUAD tissues inversely correlated with that of AVEN and predicting a favourable prognosis. Subsequent bioinformatics analysis further revealed that lncRNA-AC012236.1 functioned as an upstream regulator of hsa-miR-30d-5p. This lncRNA was found to be highly expressed in LUAD tissues, and its elevated expression was significantly associated with poor overall survival (OS) in LUAD patients. In conclusion, AVEN, as a promising diagnostic and prognostic biomarker in LUAD, affected tumour progression, immune infiltration and apoptosis resistance through the lncRNA-AC012236.1/hsa-miR-30d-5p-AVEN axis. These findings provided new insights into the pathogenesis of LUAD and highlighted potential therapeutic targets for improving patient prognosis.

This study was performed to determine the effects of human placenta mesenchymal stem cell (hPMSC) transplantation on granulosa cell apoptosis and anti-Müllerian hormone (AMH) and follicle-stimulating hormone receptor (FSHR) expression in autoimmune drug-induced premature ovarian failure (POF) mice. The aim of this research is to investigate the mechanisms of hPMSCs on ovarian reserve capacity. The POF mice model was established by injection of zona pellucida 3 peptide (pZP3). hPMSC transplantation was conducted by intravenous injection into mice following pZP3 treatment. The follicle number was examined by histopathology. The serum levels of FSH, LH, E , AMH and anti-zona pellucida antibody (AzpAb) were measured by enzyme-linked immunosorbent assay. AMH and FSHR expression in the ovary was analyzed by immunohistochemistry and western blot analysis. Granulosa cell apoptosis of the ovaries was examined by In Situ Cell Death Detection Kit. Granulosa cells were isolated and treated with SiAmh interference and hPMSC supernatant to observe the effects of AMH expression on granulosa cell apoptosis in vitro. The results showed that hPMSC transplantation can significantly recover the estrus cycle in the POF group. Morphological staining showed that the basal follicles and sinus follicles after hPMSC transplantation were higher in POF mice than in those without treatment, and the follicle number was significantly decreased with atresia. The serum levels of FSH, LH and AzpAb in the hPMSC transplantation group were reduced considerably, but the E and AMH levels were significantly increased. After hPMSC transplantation, the AMH and FSHR expression in ovarian tissue was significantly higher than in the POF group as determined by immunochemistry and western blot analysis. The FSHR expression was shown in granulosa cells only, and FSHR expression increases with AMH expressed in the ovary; granulosa cell apoptosis was decreased following hPMSC transplantation. The same results were observed from the in-vitro study. hPMSC transplantation can significantly improve the serum levels of high gonadotropin and low estrogen of POF mice, promote follicular development, inhibit excessive follicular atresia and granulosa cell apoptosis, and improve the ovarian reserve capacity. The mechanism may be achieved by increasing the expression of AMH and FSHR in ovaries.

Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes mellitus. It is characterized by progressive tubulointerstitial fibrosis. The aim of this study was to investigate the role of exosomal circular RNA (circRNAs) in regulating fibroblast growth factor 9 (FGF9) expression in DN through a competitive endogenous RNA (ceRNA) mechanism, and to reveal its potential therapeutic targets. Exosomes were isolated from serum of 3 healthy people and 3 patients with DN by ultra-fast centrifugation method, and the circRNA-miRNA-FGF9 regulatory network was constructed by combining high-throughput circRNA sequencing, bioinformatics analysis and weighted co-expression network (WGCNA). The results showed that the expression of circRNAs in serum exosomes of DN patients was significantly down-regulated, and hsa_circ_0006382 and hsa_circ_0019539 targeted the expression of FGF9 by binding to miR-34a-5p, miR-766-3p, miR-147a and miR-27a-3p. Further verification showed that the expression of FGF9 was decreased in renal tissues of DN patients (AUC = 0.902), and its recombinant protein could inhibit the expression of α-SMA and vimentin in high glucose-induced NRK-52E cells, indicating that activation of the circRNA/miRNA-FGF9 network promotes the EMT of renal tubular epithelial cells. This study revealed for the first time the mechanism of the circRNA-miRNA-FGF9 regulatory network in DN fibrosis, providing a theoretical basis for the development of diagnostic markers and targeted therapy strategies based on exosomal circRNA.

An increasing number of clinical and animal model studies indicate that activation of the innate immune system and inflammatory mechanisms are important in the pathogenesis of diabetic nephropathy. Nucleotide-binding oligomerization domain containing 2 (NOD2), a member of the NOD-like receptor family, plays an important role in innate immune response. Here we explore the contribution of NOD2 to the pathogenesis of diabetic nephropathy and found that it was upregulated in kidney biopsies from diabetic patients and high-fat diet/streptozotocin–induced diabetic mice. Further, NOD2 deficiency ameliorated renal injury in diabetic mice. In vitro, NOD2 induced proinflammatory response and impaired insulin signaling and insulin-induced glucose uptake in podocytes. Moreover, podocytes treated with high glucose, advanced glycation end-products, tumor necrosis factor-α, or transforming growth factor-β (common detrimental factors in diabetic nephropathy) significantly increased NOD2 expression. NOD2 knockout diabetic mice were protected from the hyperglycemia-induced reduction in nephrin expression. Further, knockdown of NOD2 expression attenuated high glucose–induced nephrin downregulation in vitro, supporting an essential role of NOD2 in mediating hyperglycemia-induced podocyte dysfunction. Thus, NOD2 is one of the critical components of a signal transduction pathway that links renal injury to inflammation and podocyte insulin resistance in diabetic nephropathy.

Ligustrazine has been used to alleviate clinical acute kidney injury (AKI); however, the underlying molecular mechanisms are poorly understood. In order to further elucidate the molecular mechanism underlying its occurrence, the role of nucleotide-binding oligomerization domain-containing 2 (NOD2) in AKI was investigated in the present study, and the results indicated that ligustrazine exerts an important protective effect against AKI in vivo by inhibiting the upregulation of NOD2 expression and reducing apoptosis of kidney cells following ischemia/reperfusion injury in rat models. Furthermore, the inhibitory role of ligustrazine on the upregulation of NOD2 and apoptosis of kidney cells induced by CoCl2 and oxygen and glucose deprivation followed by reoxygenation was investigated in in vitro experiments. The effect of ligustrazine on NOD2 downregulation was partially blocked by inhibiting autophagy. To the best of our knowledge, the results of the present study are the first to provide evidence that ligustrazine can inhibit NOD2-mediated inflammation to protect against renal injury, which may be in part attributed to the induction of autophagy. These findings may help design and develop new approaches and therapeutic strategies for AKI to prevent the deterioration of renal function.

Acute kidney injury (AKI) is a group of common clinical syndromes characterized by a rapid decline in renal function over a short period of time. At present, the treatment methods are limited, and research is needed to identify drugs that could alleviate renal ischemia-reperfusion (I/R) injury. Tetramethylpyrazine (TMP) is a bioactive alkaloid extracted from the Chinese herbal medicine Chuanxiong. TMP is known to possess various anti-inflammatory and cardiovascular and renal protective effects; however, the therapeutic molecular targets are still unclear. In the present study, using a rat renal I/R model, the effects of TMP on renal injury, dickkopf-1 (DKK1) expression, Wnt/[beta]-catenin signaling and apoptosis were evaluated through morphological examination, renal function tests, western blotting, immunohistochemistry and TUNEL assays. It was determined that TMP ameliorated tubular pathologic injury and improved renal function in rats following renal I/R. In addition, in rats following I/R, TMP promoted the expression of DKK1, an inhibitor of the Wnt/[beta]-catenin signaling pathway, in renal tissues, activated the Wnt/[beta]-catenin signaling pathway in kidney tissues and reduced apoptosis of renal cells. To the best of our knowledge, the present study is the first to investigate the regulatory effects of TMP on DKK1 and the Wnt/[beta]-catenin signaling pathway, revealing that TMP could attenuate AKI by activating Wnt/[beta]-catenin signaling independent of the inhibitory effect of DKK1. Key words: dickkopf-1, Wnt/[beta]-catenin pathway, tetramethylpyrazine, inflammation, renal ischemia-reperfusion injury

Acute kidney injury (AKI) is a group of common clinical syndromes characterized by a rapid decline in renal function over a short period of time. At present, the treatment methods are limited, and research is needed to identify drugs that could alleviate renal ischemia-reperfusion (I/R) injury. Tetramethylpyrazine (TMP) is a bioactive alkaloid extracted from the Chinese herbal medicine Chuanxiong. TMP is known to possess various anti-inflammatory and cardiovascular and renal protective effects; however, the therapeutic molecular targets are still unclear. In the present study, using a rat renal I/R model, the effects of TMP on renal injury, dickkopf-1 (DKK1) expression, Wnt/β-catenin signaling and apoptosis were evaluated through morphological examination, renal function tests, western blotting, immunohistochemistry and TUNEL assays. It was determined that TMP ameliorated tubular pathologic injury and improved renal function in rats following renal I/R. In addition, in rats following I/R, TMP promoted the expression of DKK1, an inhibitor of the Wnt/β-catenin signaling pathway, in renal tissues, activated the Wnt/β-catenin signaling pathway in kidney tissues and reduced apoptosis of renal cells. To the best of our knowledge, the present study is the first to investigate the regulatory effects of TMP on DKK1 and the Wnt/β-catenin signaling pathway, revealing that TMP could attenuate AKI by activating Wnt/β-catenin signaling independent of the inhibitory effect of DKK1.

The aim of the present study was to investigate the protective effect and underlying mechanism of tetramethylpyrazine (TMP) on renal ischemia reperfusion injury (RIRI) in rats, which refers to the injury caused by the restoration of blood supply and reperfusion of the kidney after a period of ischemia. Sprague-Dawley rats were randomly divided into a Sham group, renal ischemia-reperfusion (I/R) group and TMP group. TMP hydrochloride (40 mg/kg, 6 h intervals) was given via intraperitoneal injection immediately after reperfusion in the TMP group, after 24 h the kidney tissues were taken for follow-up experiments. Pathological changes in the kidney tissues were observed by periodic acid-Schiff staining. Renal function was assessed by measuring levels of serum creatinine and blood urea nitrogen, and inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6. Renal cell apoptosis was detected by TUNEL-DAPI double staining, mRNA and protein changes were analyzed by reverse transcription-quantitative PCR and western blotting. Cell viability was measured using a CCK-8 assay. It was found that the renal tissues of the sham operation group were notably abnormal, and the renal tissues of the I/R group were damaged, while the renal tissues of the TMP group were less damaged compared with those of the I/R group. Compared with the I/R group, the serum creatinine and blood urea nitrogen levels in the TMP group were low (all P<0.05), levels of inflammatory cytokines TNF-α and IL-6 decreased, the apoptotic rate was low (all P<0.05), and the relative expression levels of nucleotide-oligomerization domain-like receptor 3 (NLRP3) protein and mRNA in renal tissues were low (all P<0.05). The expression levels of hypoxia-inducible factor 1-α and NLRP3 increased after oxygen and glucose deprivation (OGD), and reduced after treatment with OGD and TMP (all P<0.05). It was concluded that TMP can reduce renal injury and improve renal function in RIRI rats, and its mechanism may be related to the reduction of NLRP3 expression in renal tissues.

Lung cancer is one of the most common types of cancer worldwide, with the highest incidence and mortality rates. Protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G) is a serine/threonine phosphatase, which is involved in the proliferation, invasion and metastasis of tumor cells. However, there are few reports on the role of PPM1G in lung adenocarcinoma (LUAD). The present study used publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases to evaluate the expression of PPM1G in LUAD, and to assess the relationship between PPM1G expression and the prognosis of patients with LUAD. Protein expression data of PPM1G obtained by immunohistochemical staining were collected from the Human Protein Atlas database. The correlation between PPM1G and immune cell infiltration and immune checkpoints was analyzed by single-sample gene set enrichment analysis of TCGA data. The Kaplan-Meier method was used for survival analysis, and univariate and multivariate Cox regression were used to analyze the effect of PPM1G on prognosis with data from TCGA database. The results showed that PPM1G was highly expressed in LUAD cancer tissues. The high expression of PPM1G was associated with poor clinical stage, T stage, N stage and overall survival in LUAD. The present study screened 29 genes related to PPM1G and closely related to the cell cycle in patients with LUAD. The expression of PPM1G was positively correlated with γδ-T cells, T helper 2 cells and natural killer CD56dim cells, and was negatively correlated with B cells, mast cells, plasmacytoid dendritic cells, T helper cells, macrophages, T cells, CD8 T cells, central memory T cells, effector memory T cells, neutrophils and T follicular helper cells. In addition, PPM1G was positively correlated with immune detection points. In conclusion, PPM1G may be involved in the control of the lung cancer cell cycle, and could be associated with prognosis and immune infiltration in patients with LUAD.