Treatment of a Patient with Acute Promyelocytic Leukemia with Multiple Isolated Relapses in the Central Nervous System: A Case Report and Mini-Review of the Literature.

The efficacy of therapeutics for acute promyelocytic leukemia (APL) has exhibited an increase in recent years. Only a few patients experience relapse, including extramedullary relapse, and in patients with extramedullary relapse, the central nervous system (CNS) is the most common site. To date, there is no expert consensus or clinical guidelines available for CNS relapse, at least to the best of our knowledge. The optimal therapeutic strategy and management options for these patients remain unclear. The present study reports the treatment of a patient with APL with multiple isolated relapses in the CNS. In addition, through a mini-review of the literature, the present study provides a summary of various reports of this disease and discusses possible treatment options for these patients.

Downregulated GPX4 in salivary gland epithelial cells contributes to salivary secretion dysfunction in Sjogren's syndrome via lipid ROS/pSTAT4/AQP5 axis.

Sjogren's syndrome (SS) is an autoimmune disease characterized by dysfunction of exocrine glands, such as salivary glands. However, the molecular mechanism of salivary secretion dysfunction in SS is still unclear. Given the significance of glutathione peroxidase 4 (GPX4) in cellular redox homeostasis, we hypothesized that dysregulation of GPX4 may play a pivotal role in the pathogenesis of salivary secretion dysfunction observed in SS. The salivary gland of SS patients and the SS mouse model exhibited reduced expression of the ferroptosis inhibitor GPX4 and the important protein aquaporin 5 (AQP5), which is involved in salivary secretion. GPX4 overexpression upregulated and GPX4 knockdown downregulated AQP5 expression in salivary gland epithelial cells (SGECs) and salivary secretion. Bioinformatics analysis of GSE databases from SS patients' salivary glands revealed STAT4 as a key intermediary regulator between GPX4 and AQP5. A higher level of nuclear pSTAT4 was observed in the salivary gland of the SS mouse model. GPX4 overexpression inhibited and GPX4 knockdown promoted STAT4 phosphorylation and nuclear translocation in SGECs. CHIP assay confirmed the binding of pSTAT4 within the promoter of AQP5 inhibiting AQP5 transcription. GPX4 downregulation accumulates intracellular lipid ROS in SGECs. Lipid ROS inhibitor ferrostatin-1 treatment during in vitro and in vivo studies confirmed that lipid ROS activates STAT4 phosphorylation and nuclear translocation in SGECs. In summary, the downregulated GPX4 in SGECs contributes to salivary secretion dysfunction in SS via the lipid ROS/pSTAT4/AQP5 axis. This study unraveled novel targets to revitalize the salivary secretion function in SS patients.

Clinical practice guidelines for prevention and treatment of postoperative gastrointestinal disorder with Integrated Traditional Chinese and Western Medicine (2023).

Postoperative gastrointestinal disorder (POGD) was a common complication after surgery under anesthesia. Strategies in combination with Traditional Chinese Medicine and Western medicine showed some distinct effects but standardized clinical practice guidelines were not available. Thus, a multidisciplinary expert team from various professional bodies including the Perioperative and Anesthesia Professional Committees of the Chinese Association of Integrative Medicine (CAIM), jointly with Gansu Province Clinical Research Center of Integrative Anesthesiology/Anesthesia and Pain Medical Center of Gansu Provincial Hospital of Traditional Chinese Medicine and WHO Collaborating Center for Guideline Implementation and Knowledge Translation/Chinese Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Center/Gansu Provincial Center for Medical Guideline Industry Technology/Evidence-based Medicine Center of Lanzhou University, was established to develop evidence-based guidelines. Clinical questions (7 background and 12 clinical questions) were identified through literature reviews and expert consensus meetings. Based on systematic reviews/meta-analyses, evidence quality was analyzed and the advantages and disadvantages of interventional measures were weighed with input from patients' preferences. Finally, 20 recommendations were developed through the Delphi-based consensus meetings. These recommendations included disease definitions, etiologies, pathogenesis, syndrome differentiation, diagnosis, and perioperative prevention and treatment.

Comparison of endovascular interventional embolization and microsurgical clipping for ruptured cerebral aneurysms: impact on patient outcomes.

OBJECTIVE: To compare the therapeutic efficacy of endovascular interventional embolization and microsurgical clipping in patients with ruptured cerebral aneurysms and investigate their subsequent influence on inflammatory indices, neurological function, prognosis, and recovery. METHODS: The two groups were compared in terms of surgery duration, hospital stay, Hunt-Hess classification, and inflammatory indices before and after the surgery, as well as National Institutes of Health Stroke Scale (NIHSS), Baethel Index (BI), and one-year prognosis of patients affected. RESULTS: The surgery duration and hospital stay of the intervention group were (116.27 ± 12.32) min and (19.82 ± 2.26) d, respectively, and those of the clipping group was (173.87 ± 10.39) min and (24.11 ± 2.33) d, respectively (both p < 0.05). Neither the intervention nor the microscopic approach had a significant impact on the severity of the patients' conditions in terms of Hunt-Hess classification (p > 0.05). In the intervention group, CRP was changed to (5.31 ± 1.22) mg/L and PCT decreased to (1.17 ± 0.39) µg/L after the surgery, while the corresponding values in clipping group were (9.78 ± 2.35) mg/L and (2.75 ± 0.81) µg/L (p > 0.05). After surgery, both groups' NIHSS scores declined dramatically, with the intervention group scoring lower than the microscopy group (6.81 ± 1.22 vs 8.72 ± 1.27) (p < 0.05). CONCLUSION: The findings of this study support the potential advantages of endovascular interventional embolization (coiling) over microsurgical clipping for the management of ruptured cerebral aneurysms. These advantages include shorter surgical duration, reduced hospital stay, lower inflammatory response, improved neurological and functional outcomes, and better long-term prognosis.

Shenhuang plaster enhances intestinal anastomotic healing in rabbits through activation of the TGF-ß and Hippo/YAP signaling pathways.

Although many efforts have been made to improve management strategies and diagnostic methods in the past several decades, the prevention of anastomotic complications, such as anastomotic leaks and strictures, remain a major clinical challenge. Therefore, new molecular pathways need to be identified that regulate anastomotic healing, and to design new treatments for patients after anastomosis to reduce the occurrence of complications. Rabbits were treated with a MST1/2 inhibitor XMU-XP-1, a Chinese medicine formula Shenhuang plaster (SHP) or a control vehicle immediately after surgery. The anastomotic burst pressure, collagen deposition, and hydroxyproline concentration were evaluated at 3 and 7 days after the surgery, and qRT-PCR and western-blot analyses were used to characterize mRNA and protein expression levels. Both XMU-XP-1 and SHP significantly increased anastomotic burst pressure, collagen deposition, and the concentration of hydroxyproline in intestinal anastomotic tissue at postoperative day 7 (POD 7). Importantly, SHP could induce TGF-ß1 expression, which activated its downstream target Smad-2 to activate the TGF-ß1 signaling pathway. Moreover, SHP reduced the phosphorylation level of YAP and increased its active form, and treatment with verteporfin, a YAP-TEAD complex inhibitor, significantly suppressed the effects induced by SHP during anastomotic tissue healing. This study demonstrated that activation of the Hippo-YAP pathway enhances anastomotic healing, and that SHP enhances both the TGF-ß1/Smad and YAP signaling pathways to promote rabbit anastomotic healing after surgery. These results suggest that SHP could be used to treat patients who underwent anastomosis to prevent the occurrence of anastomotic complications.

Tumor Promoting Function of DUSP10 in Non-Small Cell Lung Cancer Is Associated With Tumor-Promoting Cytokines.

Lung cancer, particularly non-small cell lung cancer (NSCLC) which contributes more than 80% to totally lung cancer cases, remains the leading cause of cancer death and the 5-year survival is less than 20%. Continuous understanding on the mechanisms underlying the pathogenesis of this disease and identification of biomarkers for therapeutic application and response to treatment will help to improve patient survival. Here we found that a molecule known as DUSP10 (also known as MAPK phosphatase 5) is oncogenic in NSCLC. Overexpression of DUSP10 in NSCLC cells resulted in reduced activation of ERK and JNK, but increased activation of p38, which was associated with increased cellular growth and migration. When inoculated in immunodeficient mice, the DUSP10-overexpression NSCLC cells formed larger tumors compared to control cells. The increased growth of DUSP10-overexpression NSCLC cells was associated with increased expression of tumor-promoting cytokines including IL-6 and TGFß. Importantly, higher DUSP10 expression was associated with poorer prognosis of NSCLC patients. Therefore, DUSP10 could severe as a biomarker for NSCLC prognosis and could be a target for development of therapeutic method for lung cancer treatment.

Efficient plasma metabolic fingerprinting as a novel tool for diagnosis and prognosis of gastric cancer: a large-scale, multicentre study.

OBJECTIVE: Metabolic biomarkers are expected to decode the phenotype of gastric cancer (GC) and lead to high-performance blood tests towards GC diagnosis and prognosis. We attempted to develop diagnostic and prognostic models for GC based on plasma metabolic information. DESIGN: We conducted a large-scale, multicentre study comprising 1944 participants from 7 centres in retrospective cohort and 264 participants in prospective cohort. Discovery and verification phases of diagnostic and prognostic models were conducted in retrospective cohort through machine learning and Cox regression of plasma metabolic fingerprints (PMFs) obtained by nanoparticle-enhanced laser desorption/ionisation-mass spectrometry (NPELDI-MS). Furthermore, the developed diagnostic model was validated in prospective cohort by both NPELDI-MS and ultra-performance liquid chromatography-MS (UPLC-MS). RESULTS: We demonstrated the high throughput, desirable reproducibility and limited centre-specific effects of PMFs obtained through NPELDI-MS. In retrospective cohort, we achieved diagnostic performance with areas under curves (AUCs) of 0.862-0.988 in the discovery (n=1157 from 5 centres) and independent external verification dataset (n=787 from another 2 centres), through 5 different machine learning of PMFs, including neural network, ridge regression, lasso regression, support vector machine and random forest. Further, a metabolic panel consisting of 21 metabolites was constructed and identified for GC diagnosis with AUCs of 0.921-0.971 and 0.907-0.940 in the discovery and verification dataset, respectively. In the prospective study (n=264 from lead centre), both NPELDI-MS and UPLC-MS were applied to detect and validate the metabolic panel, and the diagnostic AUCs were 0.855-0.918 and 0.856-0.916, respectively. Moreover, we constructed a prognosis scoring system for GC in retrospective cohort, which can effectively predict the survival of GC patients. CONCLUSION: We developed and validated diagnostic and prognostic models for GC, which also contribute to advanced metabolic analysis towards diseases, including but not limited to GC.

A chemotherapy-free regimen improves prognosis in elderly diffuse large B-cell lymphoma patients with a low-performance status score: A Chinese multi-center real-world study.

Background: Because patients with diffuse large B-cell lymphoma (DLBCL) aged >80 years old typically experience dismal outcomes, it is essential to improve disease control and reduce side effects in such patients. Methods: This was a multi-center retrospective study. Patients aged ≥80 years with pathologically confirmed DLBCL were treated in four centers in the Guangdong province between January 2010 and November 2020. Clinical data from patients receiving different treatment modalities were extracted from electronic medical records. Results: Finally, 50 patients aged ≥80 years were included; four (8.0%) refused treatment, 19 (38%) patients belonged to the chemotherapy-free group, and 27 (54%) patients were in the chemotherapy group. Patients receiving chemotherapy-free treatment had more often a non-germinal center B phenotype than those treated with chemotherapy (P = 0.006). The median progression-free survival (PFS) in the chemotherapy-free group was longer than that in the chemotherapy group (24.7 vs 6.3 months, P = 0.033). Good performance status (PS <2) was associated with higher PFS and overall survival (OS) (P = 0.03; P = 0.02, respectively). In patients with PS of ≥2, the median PFS and OS did not differ between the chemotherapy-free and chemotherapy groups (P = 0.391; P = 0.911, respectively). After stratifying patients with PS <2, the PFS and OS of the chemotherapy-free group were better than those of the chemotherapy group (58.1 vs 7.7 months, P = 0.006; 58.1 vs 26.5 months, P = 0.050). However, treatment-related toxicity did not differ between groups. Conclusion: PS was an independent prognostic factor of elderly DLBCL patients. Accordingly, patients aged ≥80 years with a PS of <2 could benefit from a chemotherapy-free regimen.

New insights into the occurrence of continuous cropping obstacles in pea (Pisum sativum L.) from soil bacterial communities, root metabolism and gene transcription.

BACKGROUND: Continuous cropping is a significant obstacle to sustainable development in the pea (Pisum sativum L.) industry, but the underlying mechanisms of this remain unclear. In this study, we used 16 S rDNA sequencing, transcriptomics, and metabolomics to analyze the response mechanism of roots and soil bacteria to continuous cropping and the relationship between soil bacteria and root phenotypes of different pea genotypes (Ding wan 10 and Yun wan 8). RESULTS: Continuous cropping inhibited pea growth, with a greater effect on Ding wan 10 than Yun wan 8. Metabolomics showed that the number of differentially accumulated metabolites (DAMs) in pea roots increased with the number of continuous cropping, and more metabolic pathways were involved. Transcriptomics revealed that the number of differentially expressed genes (DEGs) increased with the number of continuous cropping. Continuous cropping altered the expression of genes involved in plant-pathogen interaction, MAPK signal transduction, and lignin synthesis pathways in pea roots, with more DEGs in Ding wan 10 than in Yun wan 8. The up-regulated expression of genes in the ethylene signal transduction pathway was evident in Ding wan 10. Soil bacterial diversity did not change, but the relative abundance of bacteria significantly responded to continuous cropping. Integrative analysis showed that the bacteria with significant relative abundance in the soil were strongly associated with the antioxidant synthesis and linoleic acid metabolism pathway of pea roots under continuous cropping once. Under continuous cropping twice, the bacteria with significant relative abundance changes were strongly associated with cysteine and methionine metabolism, fatty acid metabolism, phenylpropanoid biosynthesis, terpenoid backbone biosynthesis, linoleic acid, and amino sugar and nucleotide sugar metabolism. CONCLUSION: Ding wan 10 was more sensitive to continuous cropping than Yun wan 8. Continuous cropping times and pea genotypes determined the differences in root metabolic pathways. There were common metabolic pathways in the two pea genotypes in response to continuous cropping, and the DEGs and DAMs in these metabolic pathways were strongly associated with the bacteria with significant changes in relative abundance in the soil. This study provides new insights into obstacles to continuous cropping in peas.

Integrative proteomic characterization of adenocarcinoma of esophagogastric junction.

The incidence of adenocarcinoma of the esophagogastric junction (AEG) has been rapidly increasing in recent decades, but its molecular alterations and subtypes are still obscure. Here, we conduct proteomics and phosphoproteomics profiling of 103 AEG tumors with paired normal adjacent tissues (NATs), whole exome sequencing of 94 tumor-NAT pairs, and RNA sequencing in 83 tumor-NAT pairs. Our analysis reveals an extensively altered proteome and 252 potential druggable proteins in AEG tumors. We identify three proteomic subtypes with significant clinical and molecular differences. The S-II subtype signature protein, FBXO44, is demonstrated to promote tumor progression and metastasis in vitro and in vivo. Our comparative analyses reveal distinct genomic features in AEG subtypes. We find a specific decrease of fibroblasts in the S-III subtype. Further phosphoproteomic comparisons reveal different kinase-phosphosubstrate regulatory networks among AEG subtypes. Our proteogenomics dataset provides valuable resources for understanding molecular mechanisms and developing precision treatment strategies of AEG.

GPX4 utilization by selenium is required to alleviate cadmium-induced ferroptosis and pyroptosis in sheep kidney.

Cadmium (Cd), a persistent and harmful heavy metal in the environment, can accumulate in the kidneys and cause nephrotoxicity. Selenium (Se) is a beneficial natural element that alleviates the toxicity of Cd. To ascertain the relationship between the protective mechanism of Se against Cd nephrotoxicity and ferroptosis and pyroptosis, we randomly divided 48 sheep into four groups and treated them with Cd chloride and/or sodium selenite for 50 days. The data confirmed that Cd apparently resulted in impaired kidney histology and function, depletion of GSH and nicotinamide adenine dinucleotide phosphate contents and CAT and SOD activities, elevation of MDA level, as well as the reduction in selenoprotein mRNA (GPX1, GPX4, TXNRD1, SELP) levels and GPX4 protein level and immunofluorescence intensity. Meanwhile, Cd induced ferroptosis by causing iron overload, up-regulating PTGS2, NCOA4, TFR1, and LC3B mRNA levels and PTGS2 and LC3B-II/LC3B-I protein levels, reducing SLC7A11 and FTH1 mRNA and protein levels, and enhancing the immunofluorescence co-localization of FTH1/LC3B. Moreover, it was also found that Cd triggered pyroptosis, which was evidenced by the increase of NLRP3 immunohistochemical positive signal, GSDMD-N immunofluorescence intensity, IL-1ß and IL-18 release and the levels of pyroptosis-related mRNA (NLRP3, ASC, Caspase-1, GSDMD, IL-1ß and IL-18) and proteins (NLRP3, Caspase-1p20, GSDMD-N, IL-1ß and IL-18). Notably, Se increased the expression level of GPX4 and the transcription factors TFAP2c and SP1, and ameliorated Cd-induced changes in aforementioned factors. In conclusion, GPX4 utilization by Se might be required to alleviate Cd-induced ferroptosis and pyroptosis in sheep kidney.

Selenium alleviates cadmium-induced mitophagy through FUNDC1-mediated mitochondrial quality control pathway in the lungs of sheep.

Cadmium (Cd) is a poisonous metal element that causes mitochondrial dysfunction. Selenium (Se) can reduce the damage of Cd to various organs of animals, but the protective mechanism of Se in Cd-induced lung injury has not been fully elucidated. For purpose of further illustrating the specific mechanism of Se alleviated Cd-triggered pulmonary toxicity, 48 sheep were divided into 4 groups, of which the sheep in the treatment group were taken 1 mg/kg body weight (BW) of Cd, 0.34 mg/kg BW of Se, and 0.34 mg Se + 1 mg/kg BW of Cd by intragastric administration for 50 d, respectively. The results indicated that Cd caused inflammatory cell infiltration and alveolar wall thickening, which facilitated mitochondrial vacuolation and formation of mitophagosomes in lung tissues. Simultaneously, Cd treatment impaired the antioxidant capacity of sheep lung tissue. Additionally, Cd treatment down-regulated the expression levels of mitochondrial biogenesis and mitochondrial fusion, but up-regulated the levels of mitochondrial fission and mitophagy mediated by FUNDC1. Moreover, the immunofluorescence co-localization puncta of LC3B/COX IV, LC3B/FUNDC1 were increased after Cd treatment. Nevertheless, co-treatment with Se improved effectively the above variation caused by Cd exposure. In summary, Se could mitigate Cd-generated mitophagy through FUNDC1-mediated mitochondrial quality control pathway in the lungs of sheep.

Reactive oxygen species-responsive and Raman-traceable hydrogel combining photodynamic and immune therapy for postsurgical cancer treatment.

Combining immune checkpoint blockade (ICB) therapy with photodynamic therapy (PDT) holds great potential in treating immunologically "cold" tumors, but photo-generated reactive oxygen species (ROS) can inevitably damage co-administered ICB antibodies, hence hampering the therapeutic outcome. Here we create a ROS-responsive hydrogel to realize the sustained co-delivery of photosensitizers and ICB antibodies. During PDT, the hydrogel skeleton poly(deca-4,6-diynedioic acid) (PDDA) protects ICB antibodies by scavenging the harmful ROS, and at the same time, triggers the gradual degradation of the hydrogel to release the drugs in a controlled manner. More interestingly, we can visualize the ROS-responsive hydrogel degradation by Raman imaging, given the ultrastrong and degradation-correlative Raman signal of PDDA in the cellular silent window. A single administration of the hydrogel not only completely inhibits the long-term postoperative recurrence and metastasis of 4T1-tumor-bearing mice, but also effectively restrains the growth of re-challenged tumors. The PDDA-based ROS-responsive hydrogel herein paves a promising way for the durable synergy of PDT and ICB therapy.

A Retrospective Trail Investigating Temozolomide Neoadjuvant Chemotherapy Combined with Radiotherapy in Low-Grade Pituitary Tumors.

Objective: To study and analyze the clinical application of temozolomide (TMZ) combined with radiotherapy in the treatment of low-grade pituitary tumors. Methods: A retrospective trail was conducted among 67 patients with low-grade pituitary tumors who were treated in our hospital from March 2018 to June 2020. According to different treatment methods, they were assigned into a combined group (37 cases, temozolomide capsules and radiotherapy) and a control group (30 cases, radiotherapy). The changes of serum prolactin (PRL), insulin-like growth factor-1 (IGF-1), GH levels, thyroid-stimulating hormone (TSH), serum free thyroxine (FT4), and adrenocorticotropic hormone (ACTH) were compared. Results: The chi-square test reports a significantly higher total effective rate in the combined group vs. control group (91.89% vs. 70.00%). Significant reductions in serum levels of PRL, IGF-1, and GH were observed in both groups after treatment, whereas the combined group treated with radiotherapy and TMZ resulted in significantly lower levels compared with the control group (p < 0.05). After treatment, TSH decreased, and FT4 and ACTH increased in both groups, and the treatment with radiotherapy and TMZ in the combined group led to a significantly greater amplitude of variation (p < 0.05). Conclusion: The combination of temozolomide and radiotherapy might be a promising technique for the treatment of pituitary tumors, thereby meriting promotion.

CD38 deficiency protects the retina from ischaemia/reperfusion injury partly via suppression of TLR4/MyD88/NF-κB signalling.

PURPOSE: This study aimed to explore cellular localisation of CD38 in the retina and evaluate the role and potential mechanism of CD38 deficiency in retinal ischaemia/reperfusion (I/R) injury. METHODS: Six-to eight-week-old male CD38 knockout (KO) and wild-type mice in C57BL/6 background were used. Immunostaining was performed to determine the cellular localisation of CD38 in the retina. Haematoxylin and eosin staining and immunostaining of Brn3a were used to evaluate the retinal I/R injury. Western blotting was performed to detect toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), p-p65, ionised calcium-binding adapter molecule 1, Sirtuin1 (Sirt1), Ac-p65, and pro-inflammatory cytokines protein expression. RESULTS: CD38 was highly expressed in mouse retinal microglia and astrocytes/Müller cells. CD38 deficiency reduced I/R-induced retinal damage and retinal ganglion cell death. Following retinal I/R injury, TLR4, MyD88, nuclear factor-κB p-p65 (NF-κB p-p65), pro-inflammatory cytokines and CD38 protein levels were also upregulated. After I/R injury, retinal inflammation factors IL-1ß, IL-6, and TNF-α mRNA and protein levels were increased. IL-1ß, IL-6, and TNF-α were reduced in CD38 KO mice after I/R injury. Retinal I/R injury induced the activation of microglia, but this effect was also suppressed by KO of CD38. Additionally, retinal I/R induced a significant increase in Ac-p65 protein levels and decrease in Sirt1 protein levels, while this effect was greatly attenuated by KO of CD38. CONCLUSION: CD38 deficiency protects the retina from I/R injury by suppressing microglial activation partly via activating Sirt1-mediated suppression of TLR4/MyD88/NF-κB signalling.

Construction of miRNA-mRNA-TF Regulatory Network for Diagnosis of Gastric Cancer.

Gastric cancer (GC), as an epidemic cancer worldwide, has more than 1 million new cases and an estimated 769,000 deaths worldwide in 2020, ranking fifth and fourth in global morbidity and mortality. In mammals, both miRNAs and transcription factors (TFs) play a partial role in gene expression regulation. The mRNA expression profile and miRNA expression profile of GEO database were screened by GEO2R for differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs). Then, DAVID annotated the functions of DEGs to understand the functions played in biological processes. The prediction of potential target genes of miRNA and key TFs of mRNA was performed by mipathDB V2.0 and CHEA3, respectively, and the gene list comparison was performed to look for overlapping genes coregulated by key TFs and DEMs. Finally, the obtained miRNAs, TF, and overlapping genes were used to construct the miRNA-mRNA-TF regulatory network, which was verified by RT-qPCR. 76 upregulated DEGs, 199 downregulated DEGs, and 3 upregulated miRNAs (miR-199a-3p/miR-199b-3p, miR-125b-5p, and miR-199a-5p) were identified from the expression profiles of mRNA (GSE26899, GSE29998, GSE51575, and GSE13911) and miRNA (GSE93415), respectively. Through database prediction and gene list comparison, it was found that among the 199 downregulated DEGs, 61, 71, and 69 genes were the potential targets of miR-199a-3p/miR-199b-3p, miR-125b-5p, and miR-199a-5p, respectively. 199 downregulated DEGs were used as the gene list for the prediction of key TFs, and the results showed that RFX6 ranked the highest. The potential target overlap genes of miR-199a-3p/miR-199b-3p, miR-125b-5p, and miR-199a-5p were 4 genes (SH3GL2, ATP4B, CTSE, and SORBS2), 7 genes (SLC7A8, RNASE4, ESRRG, PGC, MUC6, Fam3B, and FMO5), and 6 genes (CHGA, PDK4, TMPRSS2, CLIC6, GPX3, and PSCA), respectively. Finally, we constructed a miRNA-mRNA-TF regulatory network based on the above 17 mRNAs, 3 miRNAs, and 1 TF and verified by RT-qPCR and western blot results that the expression of RFX6 was downregulated in GC tissues. These identified miRNAs, mRNAs, and TF have a certain reference value for further exploration of the regulatory mechanism of GC.

Celastrol Attenuates RANKL-Induced Osteoclastogenesis in vitro and Reduces Titanium Particle-Induced Osteolysis and Ovariectomy-Induced Bone Loss in vivo.

Excessive bone resorption by osteoclasts contributes significantly to osteoclast-related diseases such as periprosthetic osteolysis and osteoporosis. Osteolysis in a titanium particle-induced calvarial model and bone loss in an ovariectomized mice model occurred similarly to those in humans; thus, these models can be used to evaluate potential therapies for aseptic prosthetic loosening and osteoporosis. Celastrol, which is extracted from the seeds of the genus Tripterygium, has been thoroughly investigated for its anti-inflammatory and anti-cancer pharmacological effects. However, the mechanisms involving bone metabolism by which celastrol inhibits osteoclastogenesis are not yet fully understood. We demonstrated that celastrol inhibited the receptor activator of nuclear factor κB ligand-induced osteoclastogenesis and the bone resorptive function of osteoclasts in vitro by inhibiting the activation of transforming growth factor ß-activated kinase 1-mediated NF-κB and mitogen-activated protein kinase signaling pathways and downregulating osteoclastogenesis marker-related genes. Furthermore, celastrol was also shown to be beneficial in both the titanium particle-induced osteolysis calvarial and the murine ovariectomy-induced bone loss. Collectively, our results suggested that celastrol is promising for the prevention of aseptic prosthetic loosening and osteoporosis in the treatment of osteolytic diseases induced by disrupted osteoclast formation and function.

Gastrointestinal Motility and Gut Hormone Secretion in response to Shenhuang Plaster in a Postoperative Ileus Rat Model.

Postoperative ileus (POI), a gastrointestinal function disorder, is a complication that arises from surgery. Shenhuang plaster (SHP) application to the Shenque acupoint (CV8) to promote the recovery of gastrointestinal function has achieved definite curative effects in clinical settings; however, the underlying pharmacological mechanism remains unknown. In this study, we evaluated the effects of SHP using a Sprague Dawley rat POI model. Then, gastrointestinal transit in different rat groups was evaluated by the movement of fluorescein-labelled dextran. Ghrelin, obestatin, motilin (MTL), and vasoactive intestinal peptide (VIP) plasma concentrations were measured via a radioimmunoassay. The expression of the ghrelin and obestatin receptors (GHS-R1α and GPR39) in the intestinal muscularis of rats in different groups was comparatively identified via western blotting. The results indicated that SHP application improved gastrointestinal motility in POI model rats. SHP application significantly increased ghrelin concentration and the expression of its receptor and inhibited obestatin concentration and the expression of its receptor in blood. Further, ghrelin concentration and the capability of gastrointestinal transit were positively correlated. Simultaneously, SHP application also promoted the secretion of other gastrointestinal motility hormones, such as MTL and VIP. Hence, these results provide evidence that SHP can promote the recovery of gastrointestinal transmission in POI rat models through regulation of ghrelin and other intestinal hormones.

Correlation between SNPs of PIK3CA, ERBB2 3'UTR, and their interactions with environmental factors and the risk of epithelial ovarian cancer.

OBJECTIVE: To study the correlation between SNPs at phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) rs9838117 site, erb-b2 receptor tyrosine kinase 2 (ERBB2) rs1058808 site, and their interactions with environmental factors and the epithelial ovarian cancer (EOC) risk. METHODS: Sanger sequencing was used to analyze the genotypes of PIK3CA rs9838117 and ERBB2 rs1058808 site in 587 patients with epithelial ovarian cancer (EOC). Multi-factor dimensionality reduction (MDR) was applied to analyze the interaction between PIK3CA rs9838117 and ERBB2 rs1058808 site and the clinical data. RESULTS: The risk of EOC in T allele carriers at PIK3CA rs9838117 was 1.95 times (95%CI: 1.55-2.46, P<0.01) that of G allele carriers. The risk of EOC in G allele carriers at ERBB2 rs1058808 was as 0.64 times (95%CI: 0.54-0.75, P <0.01) as the risk for C allele carriers. In the interaction model between clinical data, PIK3CA rs9838117 site and ERBB2 rs1058808 SNP site, EOC risk in high-risk combination was 3.10 times (95%CI: 1.49-6.46, P <0.01) that of low-risk combination. CONCLUSION: The SNPs at PIK3CA rs9838117 and ERBB2 rs1058808 loci were associated with the risk of EOC.

Exosomal miR-590-5p in Serum as a Biomarker for the Diagnosis and Prognosis of Gastric Cancer.

The purpose of this study is to explore the expression of miRNA-590-5p, an exosome of gastric cancer (GC), and to evaluate the suitability of miR-590-5p, an exosome with its own clinical characteristics. Serum samples from 168 gastric cancer patients and 50 matched controls were collected and exosomal RNAs were extracted. After that, miR-590-5p is analyzed by quantitative polymerase chain reaction (qRT-PCR), which is more related to clinical and pathological parameters and patient monitoring data. MGC-803 and HGC-27 cells were treated by miR-590-5p mimics, and then the changes of cell fluidity and invasiveness were monitored. The results showed that the expression level of miR-590-5p in exosomes of healthy observation group, early (I and II) stage group, and late stage (III) group was 30.34 ± 6.35, 6.19 ± 0.81, and 2.9 ± 0.19, respectively (all p < 0.05). ROC (receiver-operating characteristic curve) showed that the AUC (area under the curve) of exosomal miR-590-5p was 0.810 with 63.7% sensitivity and 86% specificity. The expression of exosomal miR-590-5p in serum was related to clinical stage (p = 0.008), infiltration depth, and the expression level of ki-67 (p < 0.001). In addition, Kaplan-Meier analysis showed that the decrease of explicit level of exosomal miR-590-5p was related to the decrease of overall survival rate (p < 0.001). Cox regression analysis showed that miR-590-5p can be used as an independent predictor. Furthermore, upregulation of miR-590-5p inhibited cell migration and invasion in MGC-803 cells and HGC-27 cells. The serum expression level of exosomal miR-590-5p may be a biomarker, which is potentially useful and noninvasive for early detection and prediction of GC. In addition, miR-590-5p can play a role in eliminating carcinogens by actively regulating the malignant potential of gastric cancer.