Apoptosis Signal-Regulated Kinase-1 Promotes Nucleus Pulposus Cell Senescence and Apoptosis to Regulate Intervertebral Disc Degeneration.

This study investigated the role of apoptosis signal-regulated kinase-1 (ASK1) in intervertebral disc degeneration (IDD). The nucleus pulposus (NP) tissues of non-IDD and IDD patients were subjected to hematoxylin and eosin, Safranin O-fast green, and immunohistochemical staining. Quantitative real-time PCR was used to assess the ASK1 mRNA level within NP tissue samples and cells. The Cell Counting Kit-8 assay, senescence-associated ß-galactosidase staining, and then flow cytometry were conducted, respectively, to assess the viability, senescence, and apoptosis of NP cells. The extracellular matrix-related factors were detected using Western blot analysis. Furthermore, the effect of ASK1 on the IDD rat model was evaluated through nuclear magnetic resonance imaging analysis, hematoxylin and eosin, Safranin O-fast green staining, and immunohistochemical staining. Finally, c-Jun N-terminal kinase (JNK) inhibitors were used to verify the effect of the JNK/p38 signaling on IDD. ASK1 mRNA and protein were up-regulated within NP tissue samples from the IDD group, IL-1ß-stimulated NP cells, and IDD rats. ASK1 inhibition promoted cell viability and repressed the senescence and apoptosis of NP cells; promoted collagen II and aggrecan; inhibited matrix metalloproteinase 3, matrix metalloproteinase 9, a disintegrin and metalloproteinase with thrombospondin motifs 4, and a disintegrin and metalloproteinase with thrombospondin motifs 5 protein levels; and increased NP cells in rat intervertebral disc tissues. ASK1 overexpression exerted the opposite effects of ASK1 inhibition on NP cells. Additionally, JNK/p38 signaling suppression could reverse the ASK1 up-regulation-induced dysfunction. In conclusion, ASK1 facilitated the senescence and apoptosis of NP cells in promoting IDD progression, which may be mediated by the JNK/p38 pathway.

Ephrin B2 (EFNB2) potentially protects against intervertebral disc degeneration through inhibiting nucleus pulposus cell apoptosis.

Nucleus pulposus (NP) cell apoptosis is a significant indication of accelerated intervertebral disc degeneration; however, the precise mechanism is unelucidated as of yet. Ephrin B2 (EFNB2), the only gene down-regulated in the three degraded intervertebral disc tissue microarray groups (GSE70362, GSE147383 and GSE56081), was screened for examination in this study. Subsequently, EFNB2 was verified to be down-regulated in degraded NP tissue samples. Interleukin-1 (IL-1ß) treatment of NP cells to simulate the IDD environment indicated that IL-1ß treatment decreased EFNB2 expression. In degenerative NP cells stimulated by IL-1ß, EFNB2 knockdown significantly increased the rate of apoptosis as well as the apoptosis-related molecules cleaved-caspase-3 and the Bax to Bcl-2 ratio. EFNB2 was found to promote AKT, PI3K, and mTOR phosphorylation; the PI3K/AKT signaling role was investigated using the PI3K inhibitor LY294002. EFNB2 overexpression significantly increased PI3K/AKT pathway activity in IL-1ß-stimulated NP cells than the normal control. Moreover, EFNB2 partially alleviated NP cell apoptosis induced by IL-1ß, reduced the cleaved-cas3 level, and decreased the Bax/Bcl-2 ratio after the addition of the inhibitor LY294002. Additionally, EFNB2 overexpression inhibited the ERK1/2 phosphorylation; the effects of EFNB2 overexpression on ERK1/2 phosphorylation, degenerative NP cell viability, and cell apoptosis were partially reversed by ERK signaling activator Ceramide C6. EFNB2 comprehensively inhibited the apoptosis of NP cells by activating the PI3K/AKT signaling and inhibiting the ERK signaling, obviating the exacerbation of IDD. EFNB2 could be a potential target to protect against degenerative disc changes.

SPTBN2 regulated by miR-214-3p inhibits the proliferation and migration of colorectal cancer cells.

Colorectal cancer (CRC) is one of the most common and lethal malignancies. According to our analysis in the GEPIA database, SPTBN2 was found to be significantly elevated in COAD patients.Western blot also verified this result, and SPTBN2 was highly expressed in two types of colorectal cancer cells, Caco2 and HCT-8. Therefore, we knocked down SPTBN2 to investigate its function in colorectal cancer, and the results of CCK-8 and Transwell assays showed that SPTBN2 deletion inhibited the proliferation, migration and invasion of CRC cells. In addition, we found that SPTBN2 may be a target of miR-214-3p through the staebase database. miR-214-3p inhibitors promote CRC cell proliferation, migration and invasion. And inhibition of SPTBN2 partially reversed the effect of miR-214-3p in CRC. Taken together, we demonstrated that SPTBN2 acts as an important target of miR-214-3p in CRC. Our study lays the foundation for the mechanism of CRC.

The comparison of short-term outcomes between robotic and laparoscopic radical distal gastrectomy.

PURPOSE: The study's objectives were to compare the short-term outcomes of robotic radical distal gastrectomy (RDG) with laparoscopic radical distal gastrectomy (LDG) for patients with gastric cancer and investigate the learning curve of RDG. METHODS: The cumulative sum (CUSUM) method was used to retrospectively analyze consecutive gastric cancer patients undergoing RDG between January 2019 and October 2021. The duration of surgery, clinical-pathological characteristics, and short-term outcomes were evaluated according to the two phases of the learning curve (learning period versus mastery period). We also compared the clinical-pathological characteristics and short-term outcomes between cases in the mastery period and LDG. RESULTS: Data from 290 patients were included in this analysis, 135 RDG and 155 LDG cases. The learning period was 20 cases. There were no significant differences in clinical-pathological characteristics between the learning period and mastery period. Compared with the learning period, the mastery period had a significant reduction in total operation time, docking time, pure operation time, and estimated blood loss, and a significant increase in hospital costs (P=0.000, 0.000, 0.000, 0.003, and 0.026, respectively). Compared with LDG, robotic cases in mastery period had a longer operative time, shorter first postoperative flatus time, and more hospital costs (P=0.000, 0.005, and 0.000, respectively). CONCLUSIONS: RGD may fasten to recover gastrointestinal function faster after the operation, can be mastered easily after a reasonable number of cases, and was associated with safe and satisfactory short-term outcomes before and after the learning curve.

Analysis of clinical efficacy and safety of hand-sewn anastomosis for the digestive tract with Da Vinci robot in rectal cancer surgery.

PURPOSE: The study aimed to analyze the clinical efficacy and safety of hand-sewn anastomosis for the digestive tract with Da Vinci robot in rectal cancer surgery. METHODS: A retrospective study was conducted to collect the clinical data from 27 patients who underwent Da Vinci robotic rectal cancer radical surgery in the department of gastrointestinal surgery at the Second Affiliated Hospital of Dalian Medical University from August 2019 to February 2022. All patients received a manual suture for digestive tract reconstruction. After the posterior wall was sutured, the anterior wall was sutured continuously. Finally, a prilling thread was used to sew the junction of the front and rear walls. Perioperative indexes and complications were recorded. RESULTS: All 27 patients successfully underwent the operation. Neither conversion to laparotomy nor perioperative death occurred. The operation time and intraoperative blood loss were 183.6 ± 44.8 min and 54.8 ± 34.4 ml, respectively. A total of 15.3 ± 7.8 lymph nodes were harvested. The pain score 24 h after operation was 1.3 ± 1.3. The time out of bed, the time to exhaust, and the time to eat were 15.6 ± 2.9 h, 2.2 ± 0.8 days, and 2.1 ± 0.6 days, respectively. A total of 4 patients (14.8%) developed complications after the operation. Grade B anastomotic leakage gradually resolved after drainage and antibiotic therapy in 1 case. A patient with grade C anastomotic leakage received a second operation for ileostomy. One patient with postoperative pneumonia recovered after anti-infective treatment. Another patient with intraperitoneal hemorrhage improved after symptomatic treatment with blood transfusion and hemostasis. The postoperative hospitalization time and total hospitalization costs were 8.9 ± 4.4 days and 89,236.1 ± 13,527.9 yuan, respectively. CONCLUSIONS: Manual suture with Da Vinci robotic surgery system is safe and feasible for reconstructing the digestive tract in rectal cancer surgery.

Nomogram for predicting prolonged postoperative ileus after laparoscopic low anterior resection for rectal cancer.

BACKGROUND: Prolonged postoperative ileus (PPOI) is a common complication after colorectal surgery that increases patient discomfort, hospital stay, and financial burden. However, predictive tools to assess the risk of PPOI in patients undergoing laparoscopic low anterior resection have not been developed. Thus, the purpose of this study was to develop a nomogram to predict PPOI after laparoscopic low anterior resection for rectal cancer. METHODS: A total of 548 consecutive patients who underwent laparoscopic low anterior resection for mid-low rectal cancer at a single tertiary medical center were retrospectively enrolled between January 2019 and January 2023. Univariate and multivariate logistic regression analysis was performed to analyze potential predictors of PPOI. The nomogram was constructed using the filtered variables and internally verified by bootstrap resampling. Model performance was evaluated by receiver operating characteristic curve and calibration curve, and the clinical usefulness was evaluated by the decision curve. RESULTS: Among 548 consecutive patients, 72 patients (13.1%) presented with PPOI. Multivariate logistic analysis showed that advantage age, hypoalbuminemia, high surgical difficulty, and postoperative use of opioid analgesic were independent prognostic factors for PPOI. These variables were used to construct the nomogram model to predict PPOI. Internal validation, conducted through bootstrap resampling, confirmed the great discrimination of the nomogram with an area under the curve of 0.738 (95%CI 0.736-0.741). CONCLUSIONS: We created a novel nomogram for predicting PPOI after laparoscopic low anterior resection. This nomogram can assist surgeons in identifying patients at a heightened risk of PPOI.

Changes in the gut microbiota of patients with Graves' orbitopathy according to severity grade.

BACKGROUND: To explore the changes of gut microbiota in Graves' orbitopathy (GO) patients of different severity grades and to identify the pathogenic bacteria of GO and the associated mechanism. METHODS: A total of 18 healthy controls and 62 GO patients were recruited. The baseline information and faecal samples of all subjects were collected for gut microbiota analysis and metabolic function prediction analysis. 16SrDNA sequencing was used for microbial diversity detection. The operational taxonomic unit (OTU) was divided using the Mothur software, and the dominant microbiota was analysed. OTU number, Chao1 index, ACE index, and Shannon index of microbiota in faecal samples were analysed using the QIIME1.9.0 software. The relative abundance of microbiota in faecal samples was analysed through principal component analysis (PCA) using the Canoco Software 5.0. The metabolic function of microbiota in faecal samples was predicted using PICRUSt 2.0. RESULTS: There was no remarkable difference in gut microbiota diversity between groups; however, the gut microbial community and dominant microbiota significantly differed among groups. Klebsiella_pneumoniae was deemed the potentially pathogenic bacteria of GO, and its abundance was positively correlated with disease severity. The metabolic prediction results revealed that inorganic nutrition metabolism, fatty acid and lipid degradation, electron transfer, aromatic compound degradation, and alcohol degradation were notably different between groups with high and low abundance of Klebsiella_pneumoniae and among groups with different GO severity grades, thereby showing a positive correlation with GO clinical risks. CONCLUSIONS: Klebsiella_pneumoniae was a potential GO-related pathogen, which may regulate the metabolic pathways to affect GO progression.

ARID1A downregulation promotes cell proliferation and migration of colon cancer via VIM activation and CDH1 suppression.

According to our prior findings, ARID1A expression is decreased in colon cancer, which has a poor prognosis. In this study, we investigated the ARID1A-VIM/CDH1 signalling axis's role in colon cancer proliferation and migration. The differentially expressed genes in cells that might be controlled by ARID1A were discovered by a database screening for ARID1A knockout. qPCR was used to analyse ARID1A and EMT markers expression levels in colon cancer. We utilized siRNA RID1A to explore the influence of ARID1A silencing on EMT in CRC cells. The function of ARID1A in the colon was investigated utilizing the wound healing, transwell and CCK-8 WST- assays. The molecular mechanism by which ARID1A regulates VIM and CDH1 was elucidated using chip-qPCR. Numerous genes involved in EMT were dysregulated in the absence of ARID1A. VIM expression increased in cells lacking ARID1A expression and vice versa. Many COAD samples with high ARID1A mRNA expression had low VIM mRNA expression, despite the relevance. CDH1 gene was positively correlated with ARID1A. Moreover, siRNA-ARID1A-transfected cells accelerated cell migration and invasion and increased cell proliferation rate in vitro. Chip-qPCR analysis showed that ARID1A binds to the promoters of both genes and changes their expression in colon cancer. ARID1A inactivation is associated with VIM activation and CDH1 suppression, which might serve as crucial molecules influencing COAD prognosis, accelerate tumour progression, and shorten patients' survival time, and promote metastases of COAD. Thus, depletion of ARID1A can be therapeutically exploited by targeting downstream effects to improve cancer treatment-related outcomes.

LncRNA H19 targets miR-22 to modulate H2 O2 -induced deregulation in nucleus pulposus cell senescence, proliferation, and ECM synthesis through Wnt signaling.

Intervertebral disc (IVD) degeneration (IDD) is a major contributor to low back pain. During IDD progression, ROS can be produced in the form of H2 O2 in nucleus pulposus cells (NPCs) in response to elevated cytokines, leading to subsequent alternations of cell fate and metabolic processes. Genetic factors are considered as main contributors to IDD pathopoiesis. Herein, we investigated the detailed function and mechanism of H19, one of the most up-regulated lncRNAs in IDD specimens, in H2 O2 -induced cell senescence model in NPCs. H19 could accelerate H2 O2 -induced degenerative changes by promoting cell senescence, increasing ADAMTS-5 and MMPs protein levels and Collagen I content, as well as suppressing NPC proliferation through activating Wnt/ß-catenin signaling. Moreover, miR-22, a direct target of H19, could bind to the 3'UTR of LEF1 to inhibit its expression and reverse the effect of H19 on NPCs, thus inhibiting Wnt/ß-catenin signaling. Taken together, H19 acts as a ceRNA to compete with LEF1 for miR-22, thus modulating downstream Wnt/ß-catenin signaling in NPCs; H19/miR-22/LEF1 might be a novel target for improving H2 O2 -induced NPC senescence and treatment for IDD.

LncRNA-RP11-296A18.3/miR-138/HIF1A Pathway Regulates the Proliferation ECM Synthesis of Human Nucleus Pulposus Cells (HNPCs).

During the process of Intervertebral disc degeneration (IDD), nucleus pulposus apoptosis increases, extracellular matrix (ECM) alters and/or degrades, abnormal proliferation of cells forms cell clusters, and the expression of various inflammatory factors increases. Thus, regulation of human nucleus pulposus cell (HNPC) proliferation and ECM synthesis present promising strategies for IDD treatment. Accumulating evidence indicates that non-coding RNAs are involved in various cellular processes, including cell proliferation, differentiation, apoptosis, and metastasis. High expression of long non-coding RNA (lncRNA) RP11-296A18.3, as well as a low expression of miR-138 during the IDD process has been reported; yet their functional roles in HNPC proliferation and ECM synthesis still remain unclear. MTT and BrdU assays showed that knockdown of RP11-296A18.3 inhibited the proliferation of HNPC. The ECM marker, MMP-13 and Collagen I expressions were also reduced. Bioinformatics target prediction, qPCR, and luciferase assays identified LncRNA-RP11-296A18.3 interacted with miR-138. Moreover, RP11-296A18.3 regulates HNPC proliferation and ECM synthesis through miR-138. As the target gene of miR-138, hypoxia-inducible factor 1-alpha (HIF1A) was closely associated with cell proliferation which was also regulated by RP11-296A18.3 via miR-138. Immunochemistry and qPCR results showed that miR-138 expression was inversely correlated to RP11-296A18.3 and HIF1A in IDD tissues, respectively; RP11-296A18.3 was positively correlated to HIF1A. We revealed that RP11-296A18.3 promote HIF1A expression through sponging miR-138, thus to promote HNPC proliferation and ECM synthesis. Targeting RP11-296A18.3 to rescue miR-138 expression in HNPCs and IDD tissues presents a promising strategy for IDD improvement. J. Cell. Biochem. 118: 4862-4871, 2017. © 2017 Wiley Periodicals, Inc.

DC - SIGNR by influencing the lncRNA HNRNPKP2 upregulates the expression of CXCR4 in gastric cancer liver metastasis.

BACKGROUND: Profiling evidences of selectin demonstrate that they play an crucial role in cancer progression and metastasis. However, DC-SIGNR as a family member of selectin participates in gastric cancer liver metastasis remains unknown. METHODS: The serum level of DC-SIGNR was evaluated in gastric cancer patients by ELISA. Manipulation DC-SIGNR expression in BGC823 and SGC7901 cell lines was mediated by lentivirus. Investigation the biological effects of DC-SIGNR were verified by MTT, wounding and transwell in vitro and experiments on animals to confirm gastric cancer liver metastasis by IVIS. Insights of the mechanism were employed microarray and bioinformatic analysis. Further to confirm the results were conducted by qRT-PCR, western blot and by flow cytometry. RESULTS: DC-SIGNR serum level was significantly increased in gastric cancer patients compared with healthy group. Additionally, DC-SIGNR level was associated with an advanced pathological stage in gastric cancer patients. DC-SIGNR knockdown inhibited the proliferation, migration and invasion of gastric cancer cells in vitro and suppressed the liver metastasis in vivo. While, DC-SIGNR overexpression promoted cell proliferation, migration and invasion. In mechanism, HNRNPKP2 as a lncRNA was upregulated after DC-SIGNR knockdown. Importantly, STAT5A promoted HNRNPKP2 expression after knockdown DC-SIGNR. Furthermore after HNRNPKP2 depletion, the downstream target gene CXCR4 was downregulated. CONCLUSIONS: DC-SIGNR promoted gastric cancer liver metastasis mediated with HNRNPKP2 which expression was regulated by STAT5A. And HNRNPKP2 decreased the expression of downstream target gene CXCR4. These findings indicated potential therapeutic candidates for gastric cancer liver metastasis.

Stress-Induced Activation of Apoptosis Signal-Regulating Kinase 1 Promotes Osteoarthritis.

Apoptosis signal-regulated kinase 1 (ASK1) has been shown to affect a wide range of cellular processes including stress-related responses, cytokine and growth factor signaling, cell cycle and cell death. Recently, we reported that lack of ASK1 slowed chondrocyte hypertrophy, terminal differentiation and apoptosis resulting in an increase in trabecular bone formation. Herein, we investigated the role of ASK1 in the pathogenesis of osteoarthritis (OA). Immunohistochemistry performed on articular cartilage samples from patients with OA showed ASK1 expression increased with OA severity. In vitro analysis of chondrocyte hypertrophy, maturation and ASK1 signaling in embryonic fibroblasts from ASK1 knockout (KO) and wild type (WT) mice was examined. Western analysis demonstrated an increase in ASK1 signaling commensurate with chondrogenic maturation during differentiation or in response to stress by the cytokines, tumor necrosis factor alpha or interleukin 1 beta in WT, but not in ASK1 KO embryonic fibroblasts. Surgically induced moderate or severe OA or OA due to natural aging in WT and ASK1 KO mice was assessed by microCT of subchondral bone, immunohistochemistry, histology, and OARSI scoring. Immunohistochemistry, microCT and OARSI scoring all indicated that the lack of ASK1 protected against OA joint degeneration, both in surgically induced OA and in aging mice. We propose that the ASK1 MAP kinase signaling cascade is an important regulator of chondrocyte terminal differentiation and inhibitors of this pathway could be useful for slowing chondrocyte maturation and cell death observed with OA progression. J. Cell. Physiol. 231: 944-953, 2016. © 2015 Wiley Periodicals, Inc.

Short-term outcome of intracorporeal ileocolonic anastomosis in patients with visceral obesity.

The primary objective of this study was to compare short-term outcomes between Intracorporeal ileocolic anastomosis (IIA) and extracorporeal ileocolic anastomosis (EIA) after laparoscopic right hemicolectomy in patients with visceral obesity. The secondary objective was to identify risk factors associated with prolonged postoperative ileus (PPOI) after laparoscopic right hemicolectomy. This single-center retrospective study analyzed visceral obesity patients who underwent laparoscopic right hemicolectomy for primary bowel cancer between January 2020 and June 2023. Patients were categorized into IIA and EIA groups based on the type of anastomosis, and a 1:1 propensity score-matched analysis was performed. A total of 129 patients were initially included in this study, with 45 patients in each group following propensity score matching. The IIA group had significantly longer anastomosis times (p < 0.001), shorter incision length (p < 0.001), and shorter length of stay (p = 0.003) than the EIA group. Meanwhile, the IIA group showed a shorter time to first flatus (p = 0.044) and quicker tolerance of a solid diet (p = 0.030). On multivariate analysis, postoperative use of opioid analgesics is an independent risk factor for PPOI (OR: 3.590 95% CI 1.033-12.477, p = 0.044), while IIA is an independent protective factor (OR: 0.195 95% CI 0.045-0.843, p = 0.029). IIA remains a safe and feasible option for visceral obesity patients. It is also associated with a quicker recovery of bowel function and shorter length of stay when compared to EIA. Additionally, IIA is an independent protective factor for PPOI.

Nomogram for predicting the surgical difficulty of laparoscopic total mesorectal excision and exploring the technical advantages of robotic surgery.

Background: Total mesorectal excision (TME), represents a key technique in radical surgery for rectal cancer. This study aimed to construct a preoperative nomogram for predicting the surgical difficulty of laparoscopic total mesorectal excision (L-TME) and to investigate whether there were potential benefits of robotic TME (R-TME) for patients with technically challenging rectal cancer. Methods: Consecutive mid-low rectal cancer patients receiving total mesorectal excision were included. A preoperative nomogram to predict the surgical difficulty of L-TME was established and validated. Patients with technically challenging rectal cancer were screened by calculating the prediction score of the nomogram. Then patients with technically challenging rectal cancer who underwent different types of surgery, R-TME or L-TME, were analyzed for comparison. Results: A total of 533 consecutive patients with mid-low rectal cancer who underwent TME at a single tertiary medical center between January 2018 and January 2021 were retrospectively enrolled. Multivariable analysis demonstrated that mesorectal fat area, intertuberous distance, tumor size, and tumor height were independent risk factors for surgical difficulty. Subsequently, these variables were used to construct the nomogram model to predict the surgical difficulty of L-TME. The area under the receiver operating characteristic curve of the nomogram was 0.827 (95% CI 0.745 - 0.909) and 0.809 (95% CI 0.674- 0.944) in the training and validation cohort, respectively. For patients with technically challenging rectal cancer, R-TME was associated with a lower diverting ileostomy rate (p = 0.003), less estimated blood loss (p < 0.043), shorter procedure time (p = 0.009) and shorter postoperative hospital stay (p = 0.037). Conclusion: In this study, we established a preoperative nomogram to predict the surgical difficulty of L-TME. Furthermore, this study also indicated that R-TME has potential technical advantages for patients with technically challenging rectal cancer.

Identification and bioinformatics analysis of genes associated with pyroptosis in spinal cord injury of rat and mouse.

The mechanism of spinal cord injury (SCI) is highly complex, and an increasing number of studies have indicated the involvement of pyroptosis in the physiological and pathological processes of secondary SCI. However, there is limited bioinformatics research on pyroptosis-related genes (PRGs) in SCI. This study aims to identify and validate differentially expressed PRGs in the GEO database, perform bioinformatics analysis, and construct regulatory networks to explore potential regulatory mechanisms and therapeutic targets for SCI. We obtained high-throughput sequencing datasets of SCI in rats and mice from the GEO database. Differential analysis was conducted using the "limma" package in R to identify differentially expressed genes (DEGs). These genes were then intersected with previously reported PRGs, resulting in a set of PRGs in SCI. GO and KEGG enrichment analyses, as well as correlation analysis, were performed on the PRGs in both rat and mouse models of SCI. Additionally, a protein-protein interaction (PPI) network was constructed using the STRING website to examine the relationships between proteins. Hub genes were identified using Cytoscape software, and the intersection of the top 5 hub genes in rats and mice were selected for subsequent experimentally validated. Furthermore, a competing endogenous RNA (ceRNA) network was constructed to explore potential regulatory mechanisms. The gene expression profiles of GSE93249, GSE133093, GSE138637, GSE174549, GSE45376, GSE171441_3d and GSE171441_35d were selected in this study. We identified 10 and 12 PRGs in rats and mice datasets respectively. Six common DEGs were identified in the intersection of rats and mice PRGs. Enrichment analysis of these DEGs indicated that GO analysis was mainly focused on inflammation-related factors, while KEGG analysis showed that the most genes were enriched on the NOD-like receptor signaling pathway. We constructed a ceRNA regulatory network that consisted of five important PRGs, as well as 24 miRNAs and 34 lncRNAs. This network revealed potential regulatory mechanisms. Additionally, the three hub genes obtained from the intersection were validated in the rat model, showing high expression of PRGs in SCI. Pyroptosis is involved in secondary SCI and may play a significant role in its pathogenesis. The regulatory mechanisms associated with pyroptosis deserve further in-depth research.

Potassium channels, tumorigenesis and targeted drugs.

Potassium channels play an important role in human physiological function. Recently, various molecular mechanisms have implicated abnormal functioning of potassium channels in the proliferation, migration, invasion, apoptosis, and cancer stem cell phenotype formation. Potassium channels also mediate the association of tumor cells with the tumor microenvironment. Meanwhile, potassium channels are important targets for cancer chemotherapy. A variety of drugs exert anti-cancer effects by modulating potassium channels in tumor cells. Therefore, there is a need to understand how potassium channels participate in tumor development and progression, which could reveal new, novel targets for cancer diagnosis and treatment. This review summarizes the roles of voltage-gated potassium channels, calcium-activated potassium channels, inwardly rectifying potassium channels, and two-pore domain potassium channels in tumorigenesis and the underlying mechanism of potassium channel-targeted drugs. Therefore, the study lays the foundation for rational and effective drug design and individualized clinical therapeutics.

The role of gut microbiota and drug interactions in the development of colorectal cancer.

The human gut microbiota is a complex ecosystem regulating the host's environmental interaction. The same functional food or drug may have varying bioavailability and distinct effects on different individuals. Drugs such as antibiotics can alter the intestinal flora, thus affecting health. However, the relationship between intestinal flora and non-antibiotic drugs is bidirectional: it is not only affected by drugs; nevertheless, it can alter the drug structure through enzymes and change the bioavailability, biological activity, or toxicity of drugs to improve their efficacy and safety. This review summarizes the roles and mechanisms of antibiotics, antihypertensive drugs, nonsteroidal anti-inflammatory drugs, lipid-lowering drugs, hypoglycemic drugs, virus-associated therapies, metabolites, and dietary in modulating the colorectal cancer gut microbiota. It provides a reference for future antitumor therapy targeting intestinal microorganisms.

Pharmacological network analysis of the functions and mechanism of kaempferol from Du Zhong in intervertebral disc degeneration (IDD).

Background: Senescence and apoptosis of the nucleus pulposus cells (NPCs) are essential components of the intervertebral disc degeneration (IDD) process. Senescence and anti-apoptosis treatments could be effective ways to delay or even stop disc degeneration. IDD has been treated with Eucommia ulmoides Oliver (Du Zhong, DZ) and its active ingredients. However, the roles and mechanisms of DZ in NPC apoptosis and senescence remain unclear. Methods: Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to select the main active ingredients of DZ with the threshold of oral bioavailability (OB) â€‹≥ â€‹30% and drug-likeness (DL) â€‹≥ â€‹0.2. GSE34095 contained expression profile of degenerative intervertebral disc tissues and non-degenerative intervertebral disc tissues were downloaded for different expression genes analysis. The disease targets genes of IDD were retrieved from GeneCards. The online tool Metascape was used for functional enrichment annotation analysis. The specific effects of the ingredient on IL-1ß treated NPC cell proliferation, cell senescence, reactive oxygen species (ROS) accumulation and cell apoptosis were determined by CCK-8, SA-ß-gal staining, flowcytometry and western blot assays. Results: A total of 8 active compounds of DZ were found to meet the threshold of OB â€‹≥ â€‹30% and DL â€‹≥ â€‹0.2 with 4151 drug targets. After the intersection of 879 IDD disease targets obtained from GeneCards and 230 DEGs obtained from the IDD-related GSE dataset, a total of 13 hub genes overlapped. According to functional enrichment annotation analysis by Metascape, these genes showed to be dramatically enriched in AGE-RAGE signaling, proteoglycans in cancer, wound healing, transmembrane receptor protein tyrosine kinase signaling, MAPK cascades, ERK1/2 cascades, PI3K/Akt signaling pathway, skeletal system, etc. Disease association analysis by DisGeNET indicated that these genes were significantly associated with IDD, intervertebral disc disease, skeletal dysplasia, and other diseases. Active ingredients-targets-signaling pathway networks were constructed by Cytoscape, and kaempferol was identified as the hub active compound of DZ. In the IL-1ß-induced IDD in vitro model, kaempferol treatment significantly improved IL-1ß-induced NPC cell viability suppression and senescence. In addition, kaempferol treatment significantly attenuated IL-1ß-induced ROS accumulation and apoptosis. Furthermore, kaempferol treatment partially eliminated IL-1ß-induced decreases in aggrecan, collagen II, SOX9, and FN1 levels and increases in MMP3, MMP13, ADAMTS-4, and ADAMTS-5. Moreover, kaempferol treatment significantly relieved the promotive effects of IL-1ß stimulation upon p38, JNK, and ERK1/2 phosphorylation. ERK1/2 inhibitor PD0325901 further enhanced the effect of kaempferol on the inhibition of ERK1/2 phosphorylation, downregulation of MMP3 and ADAMTS-4 expression, and upregulation of aggrecan and collagen II expressions. Conclusion: Kaempferol has been regarded as the major active compound of DZ, protecting NPCs from IL-1ß-induced damages through promoting cell viability, inhibiting cell senescence and apoptosis, increasing ECM production, and decreasing ECM degradation. MAPK signaling pathway may be involved. The translational poteintial of this article: This study provides in vitro experimental data support for the pharmacological effects of kaempferol in treating IDD, and lays a solid experimental foundation for its future clinical application in IDD treatment.

Biodegradable polyester-based nano drug delivery system in cancer chemotherapy: a review of recent progress (2021-2023).

Cancer presents a formidable threat to human health, with the majority of cases currently lacking a complete cure. Frequently, chemotherapy drugs are required to impede its progression. However, these drugs frequently suffer from drawbacks such as poor selectivity, limited water solubility, low bioavailability, and a propensity for causing organ toxicity. Consequently, a concerted effort has been made to seek improved drug delivery systems. Nano-drug delivery systems based on biodegradable polyesters have emerged as a subject of widespread interest in this pursuit. Extensive research has demonstrated their potential for offering high bioavailability, effective encapsulation, controlled release, and minimal toxicity. Notably, poly (ε-caprolactone) (PCL), poly (lactic-co-glycolic acid) (PLGA), and polylactic acid (PLA) have gained prominence as the most widely utilized options as carriers of the nano drug delivery system. This paper comprehensively reviews recent research on these materials as nano-carriers for delivering chemotherapeutic drugs, summarizing their latest advancements, acknowledging their limitations, and forecasting future research directions.

Comprehensive next-generation sequencing reveals double primary colorectal carcinoma missed by diagnostic imaging: A case report.

BACKGROUND: Multiple primary colorectal carcinoma (MPCC) is a rare clinical disease, which is challenging to differentiate from metastatic disease using histopathological methods. Next-generation sequencing (NGS) has been employed to identify multiple primary cancers. CASE SUMMARY: This study a rare case of a 63-year-old male patient diagnosed with MPCC by targeted NGS, which was initially missed by radiological evaluation. The patient was found to have two tumors located on the surface of the colorectum which had distinct genomic alterations. Based on wild-type KRAS detected in the unresected tumor, the patient benefited from the epidermal growth factor receptor (EGFR) inhibitor cetuximab treatment, but developed novel mutations including KIF5B-RET fusion, which provides a possible resistance mechanism to anti-EGFR therapy. CONCLUSION: Our case highlights the necessity of using genetic testing for primary tumor diagnosis and the application of serial plasma circulating tumor DNA profiling for dynamic disease monitoring.