RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stabilization.

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcription initiation and is essential for maintaining gene silencing at heterochromatic loci. Inhibition of CDK9 increases sensitivity to immunotherapy, but the underlying mechanism remains unclear. We now report that RNF20 stabilizes LSD1 via K29-mediated ubiquitination, which is dependent on CDK9-mediated phosphorylation. This CDK9- and RNF20-dependent LSD1 stabilization is necessary for the demethylation of histone H3K4, then subsequent repression of endogenous retrovirus, and an interferon response, leading to epigenetic immunosuppression. Moreover, we found that loss of RNF20 sensitizes cancer cells to the immune checkpoint inhibitor anti-PD-1 in vivo and that this effect can be rescued by the expression of ectopic LSD1. Our findings are supported by the observation that RNF20 levels correlate with LSD1 levels in human breast cancer specimens. This study sheds light on the role of RNF20 in CDK9-dependent LSD1 stabilization, which is crucial for epigenetic silencing and immunosuppression. Our findings explore the potential importance of targeting the CDK9-RNF20-LSD1 axis in the development of new cancer therapies.

SRSF1 inhibits ferroptosis and reduces cisplatin chemosensitivity of triple-negative breast cancer cells through the circSEPT9/GCH1 axis.

Cisplatin (DDP) is a commonly used chemotherapeutic agent for triple negative breast cancer (TNBC), but its efficacy can be limited by chemoresistance. This study aimed to explore the functional mechanism of SR-rich splicing factor 1 (SRSF1) in DDP chemosensitivity of TNBC cells. Levels of SRSF1, circular RNA septin 9 (circSEPT9), and GTP cyclohydrolase-1 (GCH1) in TNBC cells, DDP-resistant cells, and normal cells were determined. Cell viability, half-maximal inhibitory concentration (IC50) value, and proliferation were evaluated. Ferroptosis was determined by assay kits (ferric ion/ROS/MDA/GSH) and Western blot assay (SLC7A11/ACSL4). The genetic binding was analyzed by RNA immunoprecipitation and RNA pull-down assays. SRSF1, circSEPT9, and GCH1 were upregulated in TNBC cells. SRSF1 downregulation reduced IC50 to DDP of parent and drug-resistant TNBC cells and inhibited cell viability and proliferation, meanwhile, the downregulation reduced GSH/SLC7A11 levels while elevated ferric ion/ROS/MDA/ACSL4 levels, promoting ferroptosis. SRSF1 bound to and upregulated circSEPT9 and circSEPT9 blocked the ubiquitination of GCH1, thereby increasing GCH1 protein level. Overexpression of circSEPT9 and GCH1 attenuated the DDP chemosensitivity of TNBC cells by inhibiting ferroptosis. This study is the first to report the role of SRSF1 inhibitors combined with chemotherapy in TNBC, which provides a promising strategy for the treatment of TNBC. SIGNIFICANCE: Cisplatin (DDP) is a commonly used chemotherapeutic agent for triple negative breast cancer (TNBC), but its efficacy can be limited by chemoresistance. This study aimed to unravel the molecular mechanism of SR-rich splicing factor 1 (SRSF1) in DDP chemosensitivity of TNBC cells.

Gastric Cancer Growth Modulated by circSNTB2/miR-6938-5p/G0S2 and PDCD4.

BACKGROUND: Gastric cancer (GC) is the third most common cause of cancer-related death worldwide. Increasing studies have indicated that circular RNAs (circRNAs) play critical roles in cancer progression. However, the precise mechanism and functions of most circRNAs are still unknown in gastric cancer. METHODS: In the present study, we aim to uncover the mechanism by which circRNAs regulate gastric cancer tumorigenesis. By analyzing the microarray data, we screened differential expressed circRNAs in the gastric cancer group and identified a down-regulated circRNA, hsa_circ_0040039 (circSNTB2). Mechanically, circSNTB2 served as a sponge for the miR-6938-5p and up-regulated its expression. RESULTS: Meanwhile, G0/G1 switch gene 2 (G0S2) and programmed cell death gene 4 (PDCD4) were identified to be the aim genes of miR-6938-5p, constructing circSNTB2/miR-6938-5p/G0S2 and PDCD4 pathways. CONCLUSION: Taken together, our findings demonstrated that circSNTB2 plays an essential role in gastric cancer by regulating miR-6938-5p through G0S2 and PDCD4 genes. CircSNTB2 could be a promising biomarker for GC diagnosis and targeted therapy.

Qingchang Mixture Prevents the Intestinal Ischemia-reperfusion Injury through TLR4/NF-kB Pathway.

OBJECT: This study aims to determine the protective effect and molecular responses of the traditional Chinese medicine Qingchang mixture on intestinal ischemia-reperfusion (IR) injury. METHODS: The rat intestinal IR model was prepared. The intestinal ischemic injury was evaluated by HE staining, biochemical assay and western blot. In addition, a human hypoxia-reoxygenation (HR) in vitro model was prepared using intestinal epithelial cells (IEC-6). The viability and apoptosis of IEC-6 cells were measured by CCK8 and apoptosis detection. TAK242 or PDTC was used as a small molecule inhibitor of TLR4 or NF-κB, respectively. RESULTS: Compared with the IR group, the pretreatment of the Qingchang mixture reduced the morphological damage, oxidative stress, inflammatory response, and barrier function damage of the small intestine tissue. IR significantly increased the expression of TLR4 and NF-κB, while the pretreatment of the Qingchang mixture inhibited the expression of TLR4 and NF-κB. Furthermore, the pretreatment of Qingchang mixture, TAK242, or PDTC effectively improved the viability and hindered apoptosis of the HR-induced IEC-6 cells. CONCLUSIONS: Traditional Chinese medicine Qingchang mixture prevents intestinal IR injury through TLR4/NF-kB pathway.

Rhubarb Peony Decoction Downregulates the Expression of c-Fos after Intestinal Epithelial Cells Hypoxia-reoxygenation Injury.

BACKGROUND: Intestinal ischemia-reperfusion (I/R) injury occurs in several clinical situations and after intestinal transplantation. This study aimed to examine the role of rhubarb peony decoction (RPD) in intestinal I/R injury. METHODS: Different concentrations of RPD were set to treat IEC-6 and Caco-2 cells. Cell proliferation and apoptosis were measured by CCK-8 and flow cytometry assays. High-throughput transcriptome sequencing was performed on IEC-6 cells treated with hypoxia-reoxygenation (HR) or HR and RPD. RESULTS: RPD treatment significantly promoted the proliferation of IEC-6 and Caco-2 cells and inhibited apoptosis. Sequencing results identified 109 significantly up-regulated genes and 36 significantly down-regulated genes in the RPD group. In addition, the results of western blot suggested that HR induced the expression of c-Fos, and the treatment of RPD prevented the HR-induced c- Fos expression. Importantly, knockdown of c-Fos rescued the HR-inhibited cell proliferation and HR-induced apoptosis. CONCLUSIONS: In conclusion, RPD was beneficial in protecting the survival of intestinal epithelial cells under HR stress. Furthermore, the increase in c-Fos expression after HR stress was closely related to the proliferation and apoptosis of intestinal epithelial cells.

Laparoscopic resection of a rare diaphragmatic haemangioma: a case report.

This case report describes the laparoscopic resection of a rare diaphragmatic haemangioma. A 45-year-old male patient was diagnosed incidentally with a left subphrenic mass by computed tomography. Laparoscopic left subphrenic mass excision was performed under general anaesthesia. A phrenic haemangioma was confirmed by postoperative pathology. Tumours originating in the diaphragm are rare, with only approximately 200 cases reported in the past century. The diaphragmatic tumour was determined to be primary because intraoperative imaging showed that the tumour was relatively isolated and had no obvious relationship with the surrounding tissues and organs.

Paralytic ileus as first symptom of Miller Fisher syndrome: A case report.

INTRODUCTION: Miller Fisher syndrome (MFS), regarded by many scholars as a variant of Guillain Barre syndrome (GBS), accounts for approximately 5% to 10% of GBS cases. The typical clinical manifestations of MFS are extraocular muscle paralysis, ataxia, and tendon reflex loss or disappearance. To date, intestinal obstruction has rarely been reported as the initial symptom. PATIENT CONCERNS: A 48-year-old woman presenting with abdominal pain and distention was diagnosed with paralytic ileus. There was no significant improvement in symptoms after symptomatic treatment. After that, the patient developed visual rotation, with limited binocular abduction and adduction, and ataxia. Anti-ganglioside testing revealed positive anti-ganglioside antibodies. DIAGNOSIS: The patient was diagnosed as MFS. INTERVENTIONS: The early stage is mainly symptomatic treatment of paralytic ileus. After MFS was diagnosed, the patient was given large amounts of immunoglobulin and hormone shock therapy. OUTCOMES: After 1 week, the symptoms of intestinal obstruction and MFS gradually improved. The patient was later discharged automatically for financial reasons. Six months after discharge, the patient was interviewed by telephone, and she had recovered. CONCLUSION: To date, intestinal obstruction has rarely been reported as the initial symptom. In case of inconsistencies between the imaging examinations and clinical symptoms, neuroelectrophysiology and cerebrospinal fluid puncture should be performed, striving for timely detection and treatment.

Protective mechanisms of Agrimonia pilosa Ledeb in dextran sodium sulfate-induced colitis as determined by a network pharmacology approach.

Previous studies reported that Agrimonia pilosa (AP) Ledeb possessed diverse biological activities, including anti-inflammatory, antioxidant, and anti-tumor activities. However, the effect of AP on ulcerative colitis (UC) remains unclear. In this study, we investigated the therapeutic effect and mechanisms of AP on dextran sodium sulfate (DSS)-induced colitis. The potential constituents of AP were investigated by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). A total of 13 compounds were recognized by UPLC-Q-TOF/MS chromatogram. Furthermore, a network pharmacology approach revealed that there are 297 candidate targets of UC and 549 common targets for the 13 active ingredients of AP. GO enrichment and KEGG pathway analysis indicated that AP might have a protective effect on UC through the nuclear factor κB (NF-κB) and nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathways. Subsequent experimental validation in a DSS-induced colitis model revealed that AP alleviated the severity of DSS-induced colitis, reduced the production of proinflammatory factors, and protected against the loss of intestinal integrity. Moreover, AP inhibited the phosphorylation of NF-κB p65 and the activation of the NLRP3 inflammasome. In conclusion, AP ameliorated DSS-induced colitis through suppressing the activation of the NLRP3 inflammasome and NF-κB signaling pathways.

Transcutaneous Electrical Acupoint Stimulation for Improving Postoperative Recovery, Reducing Stress and Inflammatory Responses in Elderly Patient Undergoing Knee Surgery.

Transcutaneous electrical acupoint stimulation (TEAS) is a form of acupuncture treatment that applies electrical stimulation on specific acupoint through cutaneous electrodes. This technique has been used for perioperative anesthesia management as part of after surgery recovery. However, to date, limited data are available for using the TEAS for postoperative recovery in elderly surgical patients. We conducted this prospective randomized sham-control trail to evaluate the efficacy of TEAS in a group of elderly patients receiving knee surgery under epidural anesthesia. 52 subjects were assigned to either the experimental group (Group E) or control group (Group C). The patients in Group E received TEAS at zusanli (ST36), sanyinjiao (SP6), neiguan (PC6), and quchi acupoints (LI11) 30min prior to the epidural anesthesia and postoperative day 1 and 2, while patients in Group C received sham TEAS on the same acupoints for 30min same as those of Group E. The primary endpoint was the Quality of Recovery-40 questionnaire (QR-40) and the secondary endpoints were the biomarkers level of stress and inflammatory responses and visual analogue scale (VAS). A one-way ANOVA (SNK method) was used in statistic, and p<0.05 is considered to be statistically significant. Our data showed that the QoR-40 was significantly lower in Group C than that in Group E at postoperative day 1 (p<0.05); Similarly, Cortisol (COR), Adrenocorticotropic Hormone (ACTH), and C-reactive protein (CRP) were significantly lower in Group E than those of Group C at postoperative day 1, 3, and 7 (p<0.05), while the neutrophil/lymphocyte ratio (N/L) was lower in Group E than that in Group C at postoperative day 1 and 3 (p<0.05). Our results showed that perioperative TEAS administration is able to facilitate the development of postoperative recovery of elderly patients, especially at the early stage after surgery. The reported results are likely to be mediated by the reduction of surgical inflammation and perioperative stress response.

Sichong formula inhibits the proliferation and migration of human gastric cancer cells.

PURPOSE: Traditional Chinese medicine (TCM) has gained increasing attention for the treatment of multiple chronic diseases, such as cancer. Here we aim to identify the antitumor activity of Sichong formula, a novel TCM, in human gastric cancer cells and investigate the underlying mechanisms. METHODS: The AGS and MKN45 gastric cancer cells were treated with Sichong formula at different concentrations. The proliferation rates were tested by CCK-8 and colony formation assays. Cell migration and invasion were tested by scratch and transwell assays. Gelatin zymography was used to detect the matrix metalloproteinase 9 (MMP9) activity in cell suspendents. Cell apoptosis was analyzed by Annexin V/PI staining and flow cytometry. The expression of interest proteins was tested by Western blot. RESULTS: Cell proliferation analysis indicated that Sichong formula inhibited cell viability of AGS and MKN45 cells in a dose- and time-dependent manner. The IC50 values were 240 µg/mL and 200 µg/mL for AGS and MKN45 cells, respectively. Furthermore, we found that Sichong formula could inhibit the invasion and migration of gastric cancer cells, which might be mediated by the downregulation of MMP9 activity. Flow cytometry results indicated that Sichong formula induced apoptosis in gastric cancer cells through upregulation of Bax/Bcl2 ratio and activation of caspase cascade. The results from Western blot indicated that Sichong formula resulted in cell autophagy and inactivation of AKT signaling pathway. CONCLUSION: Our data suggest that Sichong formula inhibits the proliferation and migration and induces apoptosis in human gastric cancer cells. The inhibitory effect of Sichong formula was, at least partly, mediated by cell autophagy and AKT pathway.