Dysregulation of the Gut Microbiota Contributes to Sevoflurane-Induced Cognitive Dysfunction in Aged Mice by Activating the NLRP3 Inflammasome.

Postoperative cognitive dysfunction (POCD), a common complication in elderly patients after surgery, seriously affects patients' quality of life. Long-term or repeated inhalation of sevoflurane can cause neuroinflammation, which is a risk factor for POCD. However, the underlying mechanism needs to be further explored. Recent research had revealed a correlation between neurological disorders and changes in the gut microbiota. Dysfunction of the gut microbiota is involved in the occurrence and development of central nervous system diseases. Here, we found that cognitive dysfunction in aged mice induced by sevoflurane exposure (3%, 2 hours daily, for 3 days) was related to gut microbiota dysbiosis, while probiotics improved cognitive function by alleviating dysbiosis. Sevoflurane caused a significant decrease in the abundance of Akkermansia (P<0.05), while probiotics restored the abundance of Akkermansia. Compared to those in the control group, sevoflurane significantly increased the expression of NLRP3 inflammasome-associated proteins in the gut and brain in the sevoflurane-exposed group, thus causing neuroinflammation and synaptic damage, which probiotics can mitigate (con vs. sev, P < 0.01; p+sev vs. sev, P < 0.05). In conclusion, for the first time, our study revealed that dysbiosis of the gut microbiota caused by sevoflurane anesthesia contributes to the NLRP3 inflammasome-mediated neuroinflammation and cognitive dysfunction from the perspective of the gut-brain axis. Perhaps postoperative cognitive impairment in elderly patients can be alleviated or even prevented by regulating the gut microbiota. This study provides new insights and methods for the prevention and treatment of cognitive impairment induced by sevoflurane.

GINS1 promotes ZEB1-mediated epithelial-mesenchymal transition and tumor metastasis via ß-catenin signaling in hepatocellular carcinoma.

GINS1 regulates DNA replication in the initiation and elongation phases and plays an important role in the progression of various malignant tumors. However, the role of GINS1 in hepatocellular carcinoma (HCC) remains largely unclear. In this study, we investigated the role and underlying mechanisms of GINS1 in contributing to HCC metastasis. We found that GINS1 was significantly upregulated in HCC tissues and cell lines, especially in HCC tissues with vascular invasion and HCC cell lines with highly metastatic properties. Additionally, high expression of GINS1 was positively correlated with the progressive clinical features of HCC patients, including tumor number (multiple), tumor size (>5 cm), advanced tumor stage, vascular invasion and early recurrence, suggesting that GINS1 upregulation was greatly involved in HCC metastasis. Moreover, Kaplan-Meier survival analysis revealed that high GINS1 expression predicted a poor prognosis. Both in vitro and in vivo, silencing of GINS1 inhibited proliferation, migration, invasion and metastasis, while overexpression of GINS1 induced opposite effects. Mechanistically, we found that ZEB1 was a crucial regulator of GINS1-induced epithelial-mesenchymal transition (EMT), and GINS1 promoted EMT and tumor metastasis through ß-catenin signaling. Overall, the present study demonstrated that GINS1 promoted ZEB1-mediated EMT and tumor metastasis via ß-catenin signaling in HCC.

Metabolic Reprogramming in Gliocyte Post-cerebral Ischemia/ Reperfusion: From Pathophysiology to Therapeutic Potential.

Ischemic stroke is a leading cause of disability and death worldwide. However, the clinical efficacy of recanalization therapy as a preferred option is significantly hindered by reperfusion injury. The transformation between different phenotypes of gliocytes is closely associated with cerebral ischemia/ reperfusion injury (CI/RI). Moreover, gliocyte polarization induces metabolic reprogramming, which refers to the shift in gliocyte phenotype and the overall transformation of the metabolic network to compensate for energy demand and building block requirements during CI/RI caused by hypoxia, energy deficiency, and oxidative stress. Within microglia, the pro-inflammatory phenotype exhibits upregulated glycolysis, pentose phosphate pathway, fatty acid synthesis, and glutamine synthesis, whereas the anti-inflammatory phenotype demonstrates enhanced mitochondrial oxidative phosphorylation and fatty acid oxidation. Reactive astrocytes display increased glycolysis but impaired glycogenolysis and reduced glutamate uptake after CI/RI. There is mounting evidence suggesting that manipulation of energy metabolism homeostasis can induce microglial cells and astrocytes to switch from neurotoxic to neuroprotective phenotypes. A comprehensive understanding of underlying mechanisms and manipulation strategies targeting metabolic pathways could potentially enable gliocytes to be reprogrammed toward beneficial functions while opening new therapeutic avenues for CI/RI treatment. This review provides an overview of current insights into metabolic reprogramming mechanisms in microglia and astrocytes within the pathophysiological context of CI/RI, along with potential pharmacological targets. Herein, we emphasize the potential of metabolic reprogramming of gliocytes as a therapeutic target for CI/RI and aim to offer a novel perspective in the treatment of CI/RI.

Factors influencing the efficacy of ultrasound-guided extracorporeal shockwave lithotripsy in the treatment of ureteral stones: a retrospective study.

The aim of the study was to analyze the factors influencing the efficacy of ultrasound-guided extracorporeal shockwave lithotripsy (ESWL) in the treatment of ureteral stones. The clinical data of 8102 patients (6083 men and 2019 women) who presented with ureteral stones were retrospectively analyzed. All the patients were treated with ultrasound-guided ESWL. The stone-free rate (SFR) was calculated to evaluate the effect of ESWL. The characteristics of the patients and their stones, and the ESWL parameters applied were compared to identify the factors affecting the treatment outcomes. The SFR and that following one ESWL session were 94.6% (7663/8102) and 75.4% (6107/8102), respectively. Multivariate analysis showed that stone location (OR 0.656, p < 0.001), stone size (OR 1.103, p < 0.001), and degree of hydronephrosis (OR 1.952, p < 0.001) independently affected SFR; and age (OR 1.005, p = 0.022), stone location (OR 0.729, p < 0.001), stone size (OR 1.103, p < 0.001), degree of hydronephrosis (OR 1.387, p = 0.001), maximum energy level(OR 0.691, p < 0.001) independently affected SFR following one session. Ultrasound-guided ESWL is effective in all levels of ureteral stones. Large stone size and moderate hydronephrosis are correlated with treatment failure. Ultrasound-guided ESWL may be the first choice for distal ureteral stones.

hsa_circ_0002980 prevents proliferation, migration, invasion, and epithelial-mesenchymal transition of liver cancer cells through microRNA-1303/cell adhesion molecule 2 axis.

BACKGROUND: Liver cancer (LC) is a rare malignancy. Circular RNA (circRNA) dysregulation is associated with LC metastasis. hsa_circ_0002980 was found to be unexpectedly downregulated in LC tissues; however, its specific function remains unclear. METHODS: hsa_circ_0002980 expression was confirmed using RT-qPCR. The effects of circ_0002980 on the proliferation, metastasis, and EMT-related proteins of LC cells were assessed using clone formation, flow cytometry, Transwell assays, and Western blotting. The relationship between circ_0002980 and miR-1303 or miR-1303 and CADM2 was analyzed using a dual-luciferase reporter assay. Thereafter, the influence of these three genes on LC cell progression was determined through rescue experiments. RESULTS: hsa_circ_0002980 expression was lower in LC. circ_0002980 overexpression inhibited the proliferation, migration, invasion, and EMT of LC cells. In addition, circ_0002980 specifically binds to miR-1303, and the accelerated effect of miR-1303 overexpression on LC progression was partially reversed by circ_0002980. Moreover, miR-1303 can also target CADM2, and CADM2-mediated prevention can also be attenuated by miR-1303 overexpression. CONCLUSIONS: In LC cells, circ_0002980 upregulation prevents cell proliferation, metastasis, and EMT by affecting the miR-1303/CADM2 axis. Therefore, this axis may be a novel therapeutic target in LC.

A DNA/RNA heteroduplex oligonucleotide coupling asparagine depletion restricts FGFR2 fusion-driven intrahepatic cholangiocarcinoma.

Pemigatinib, a pan-FGFR inhibitor, is approved to treat intrahepatic cholangiocarcinoma (ICC) harboring FGFR2 fusion mutations. Improving its targeting of FGFR2 fusions remains an unmet clinical need due to its pan selectivity and resistance. Here, we report a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting the chimeric site in FGFR2-AHCYL1 (F-A Cho-HDO) that accumulates in ICC through endocytosis of low-density lipoprotein receptor (LDLR), which is highly expressed in both human and murine ICC. F-A Cho-HDO was determined to be a highly specific, sustainable, and well-tolerated agent for inhibiting ICC progression through posttranscriptional suppression of F-A in ICC patient-derived xenograft mouse models. Moreover, we identified an EGFR-orchestrated bypass signaling axis that partially offset the efficacy of F-A Cho-HDO. Mechanistically, EGFR-induced STAT1 upregulation promoted asparagine (Asn) synthesis through direct transcriptional upregulation of asparagine synthetase (ASNS) and dictated cell survival by preventing p53-dependent cell cycle arrest. Asn restriction with ASNase or ASNS inhibitors reduced the intracellular Asn, thereby reactivating p53 and sensitizing ICC to F-A Cho-HDO. Our findings highlight the application of genetic engineering therapies in ICC harboring FGFR2 fusions and reveal an axis of adaptation to FGFR2 inhibition that presents a rationale for the clinical evaluation of a strategy combining FGFR2 inhibitors with Asn depletion.

Orexin A alleviates LPS-induced acute lung injury by inhibiting macrophage activation through JNK-mediated autophagy.

Crosstalk between the central nervous system and immune system by the neuroendocrine and autonomic nervous systems is critical during the inflammatory response. Exposure to endotoxin alters the activity of hypothalamic homeostatic systems, resulting in changed transmitter release within the brain. This study investigated the effects and cellular molecular mechanisms of neurogenic and exogenous orexin-A (OXA) in LPS-induced acute lung injury (ALI). We found the production of OXA in the hypothalamus and lungs was both decreased following LPS infection. LPS-induced lung injury including the destruction of the structure, inflammatory cell infiltration, and pro-inflammatory cytokines generation was aggravated in mice in which orexin neurons were lesioned with the neurotoxin orexin-saporin (orexin-SAP). Administration of exogenous OXA greatly improved lung pathology and reduced inflammatory response. Orexin receptors were found in cultured mouse bone marrow-derived macrophages (BMDMs) and lung macrophages (LMs), adoptive transfer of OXA-treated macrophages showed alleviative lung injury compared to adoptive transfer of macrophages without OXA treatment. Mechanistically, it is the induction of autophagy via JNK activation that is responsible for OXA to suppress macrophage-derived pro-inflammatory cytokine production. These findings highlight the importance of neuro-immune crosstalk and indicate that OXA may be a potential therapeutic agent in the treatment of ALI.

Astragaloside IV inhibits AOM/DSS-induced colitis-associated tumorigenesis via activation of PPARγ signaling in mice.

BACKGROUND: Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD), resulting from long-term inflammation in the intestines. The primary cause of CAC is the imbalance of oxidative metabolism in intestinal cells, triggered by excessive reactive oxygen (ROS) and nitrogen (NO) species production due to prolonged intestinal inflammation. This imbalance leads to genomic instability caused by DNA damage, eventually resulting in the development of intestinal cancer. Previous studies have demonstrated that astragaloside IV is effective in treating dextran sulfate sodium salt (DSS)-induced colitis, but there is currently no relevant research on its efficacy in treating CAC. METHODS: To investigate the effect of astragaloside IV against CAC and the underlying mechanism, C57 mice were treated with (20, 40, 80 mg/kg) astragaloside IV while CAC was induced by intraperitoneal injection of 10 mg/kg azoxymethane (AOM) and ad libitum consumption of 2% dextran sulfate sodium salt (DSS). We re-verified the activating effects of astragaloside IV on PPARγ signaling in IEC-6 cells, which were reversed by GW9662 (the PPARγ inhibitor). RESULTS: Our results showed that astragaloside IV significantly improved AOM/DSS-induced CAC mice by inhibiting colonic shortening, preventing intestinal mucosal damage, reducing the number of tumors and, the expression of Ki67 protein. In addition, astragaloside IV could activate PPARγ signaling, which not only promoted the expression of Nrf2 and HO-1, restored the level of SOD, CAT and GSH, but also inhibited the expression of iNOS and reduced the production of NO in the intestine and IEC-6 cells. And this effect could be reversed by GW9662 in vitro. Astragaloside IV thus decreased the level of ROS and NO in the intestinal tract of mice, as well as reduced the damage of DNA, and therefore inhibited the occurrence of CAC. CONCLUSION: Astragaloside IV can activate PPARγ signaling in intestinal epithelial cells and reduces DNA damage caused by intestinal inflammation, thereby inhibiting colon tumourigenesis. The novelty of this study is to use PPARγ as the target to inhibit DNA damage to prevent the occurrence of CAC.

A novel prognostic biomarker: GINS3 is correlated with methylation and immune escape in liver hepatocellular carcinoma.

Background: Liver cancer remains one of the tricky malignancies nowadays. GINS complex subunit 3 (GINS3), part of the GINS tetrameric complex, is significantly upregulated in many cancers, including liver hepatocellular carcinoma (LIHC). With the development of liver cancer treatment, immune and molecular targeted therapy gradually becomes a promising treatment. However, the key target for liver cancer is still indistinct. Herein, the underneath mechanism of GINS3 was investigated to verify its role as a biomarker in LIHC. Methods: Genomic expression, genetic alteration, and methylation analyses were obtained from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), The University of Alabama at Birmingham CANcer (UALCN), and Human Protein Atlas (HPA), cBioPortal, and MethSurv databases. Subsequently, the diagnostic and prognostic role of GINS3 in LIHC were analyzed based on data from receiver operating characteristic (ROC), Kaplan-Meier plotter (KM-plotter), and univariate and multivariate cox regression analyses. The functional analyses were conducted with GeneMANIA and STRING databases, gene-gene, and protein-protein interaction (PPI) networks, Gene Ontology (GO) term, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Tumor Immune Estimation Resource (TIMER), Tumor-Immune System Interaction Database (TISIDB), and Gene Expression Profiling Interactive Analysis (GEPIA) were utilized to explore the internal connection with the immune escape. Results: Through the analyses of genomic expression, GINS3 was significantly upregulated in LIHC and positively correlated with higher T classification. ROC analysis indicated GINS3 as a potential biomarker in the diagnosis of LIHC. KM-plotter, univariate and multivariate cox regression analyses both associated GINS3 with poor prognosis in LIHC patients. GINS3 genetic alteration, gene-gene interaction, PPI networks, and enrichment analysis further revealed that GINS3 played a pivotal role in the progression of LIHC. Furthermore, hypermethylation of GINS3 at different cytosine-guanine (CpG) sites was correlated with better or worse overall survival (OS) in LIHC and GINS3 was also closely correlated with m6A modification. Moreover, results supported that GINS3 could influence the tumor microenvironment and relate to the immune checkpoints. Conclusions: Taken together, comprehensive analyses from this study supported GINS3 as a novel targeted biomarker in LIHC.

Non-coding RNAs in breast cancer: with a focus on glucose metabolism reprogramming.

Breast cancer is the tumor with the highest incidence in women worldwide. According to research, the poor prognosis of breast cancer is closely related to abnormal glucose metabolism in tumor cells. Changes in glucose metabolism in tumor cells are an important feature. When sufficient oxygen is available, cancer cells tend to undergo glycolysis rather than oxidative phosphorylation, which promotes rapid proliferation and invasion of tumor cells. As research deepens, targeting the glucose metabolism pathway of tumor cells is seen as a promising treatment. Non-coding RNAs (ncRNAs), a recent focus of research, are involved in the regulation of enzymes of glucose metabolism and related cancer signaling pathways in breast cancer cells. This article reviews the regulatory effect and mechanism of ncRNAs on glucose metabolism in breast cancer cells and provides new ideas for the treatment of breast cancer.

Brain network mechanism on cognitive control task in the elderly with brain aging: A functional near infrared spectroscopy study.

Objective: To study the brain network mechanism of cognitive control in the elderly with brain aging. Materials and methods: 21 normal young people and 20 elderly people were included in this study. Mini-mental State Examination and functional near-infrared spectroscopy (fNIRS) synchronous judgment test (including forward tests and reverse judgment tests) were performed on all subjects. To observe and compare differences in brain region activation and brain functional connectivity between subjects and forward and reverse trials by recording functional connectivity (FC) in different task paradigms and calculating bilateral prefrontal and primary motor cortical (PMC) areas. Results: In the forward and reverse judgment tests, the reaction time of the elderly group was significantly longer than the young group (P < 0.05), and there was no significant difference in the correct rate. In the homologous regions of interest (ROI) data, the FC of PMC and prefrontal cortex (PFC) in the elderly group was significantly decreased (P < 0.05). In the heterologous ROI data, except for left primary motor cortex (LPMC)-left prefrontal cortex (LPFC), the other PMC and PFC of the elderly group were significantly lower than the young group (P < 0.05) while processing the forward judgment test. However, the heterologous ROI data of LPMC-right prefrontal cortex (RPFC), LPMC-LPFC and RPFC-LPFC in the elderly group were significantly lower than the young group (P < 0.05) while processing the reverse judgment test. Conclusion: The results suggest that brain aging affected degeneration of whole brain function, which reduce the speed of information processing and form a brain network functional connection mode different from that of young people.

Minocycline Attenuates Sevoflurane-Induced Postoperative Cognitive Dysfunction in Aged Mice by Suppressing Hippocampal Apoptosis and the Notch Signaling Pathway-Mediated Neuroinflammation.

Postoperative cognitive dysfunction (POCD), an important postoperative neurological complication, is very common and has an elevated incidence in elderly patients. Sevoflurane, an inhaled anesthetic, has been demonstrated to be associated with POCD in both clinical and animal studies. However, how to prevent POCD remains unclear. Minocycline, a commonly used antibiotic can cross the blood-brain barrier and exert an inhibitory effect on inflammation in the central nervous system. The present work aimed to examine the protective effect and mechanism of minocycline on sevoflurane-induced POCD in aged mice. We found that 3% sevoflurane administered 2 h a day for 3 consecutive days led to cognitive impairment in aged animals. Further investigation revealed that sevoflurane impaired synapse plasticity by causing apoptosis and neuroinflammation and thus induced cognitive dysfunction. However, minocycline pretreatment (50 mg/kg, i.p, 1 h prior to sevoflurane exposure) significantly attenuated learning and memory impairments associated with sevoflurane in aged animals by suppressing apoptosis and neuroinflammation. Moreover, a mechanistic analysis showed that minocycline suppressed sevoflurane-triggered neuroinflammation by inhibiting Notch signaling. Similar results were also obtained in vitro. Collectively, these findings suggested minocycline may be an effective drug for the prevention of sevoflurane-induced POCD in elderly patients.

Laparoscopic Common Bile Duct Exploration in Patients with a Previous History of Biliary Tract Surgery.

For recurrent choledocholithiasis, abdominal adhesions in previous surgeries lead to changes in anatomical structures, and a secondary injury occurs easily when performing another operation for laparoscopic common bile duct exploration (LCBDE), which was once considered a relative contraindication. In view of the limitations of the current surgical technique, this study summarized the surgical approaches and crucial anatomical landmarks for reoperation for LCBDE. Four general surgical approaches were proposed to expose the common bile duct, including the ligamentum teres hepatis approach, the anterior hepatic duodenal ligament approach, the right hepatic duodenal ligament approach, and the hybrid approach. Additionally, this study highlighted seven crucial anatomical landmarks: the parietal peritoneum, the gastrointestinal serosa, the ligamentum teres hepatis, the inferior margin of the liver, the gastric antrum, the duodenum, and the hepatic flexure of the colon, which were helpful to safely separate abdominal adhesions and expose the common bile duct. Moreover, to shorten the time of choledocholithotomy, a sequential method was innovatively applied for the removal of the stones in common bile duct. Mastering the above surgical approaches, including identifying crucial anatomical landmarks and adopting the sequential method will improve the safety of reoperation for LCBDE, shorten the operation time, promote the fast recovery of patients, reduce postoperative complications, and contribute to the popularization and application of this technique.

Gegen Qinlian decoction activates AhR/IL-22 to repair intestinal barrier by modulating gut microbiota-related tryptophan metabolism in ulcerative colitis mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Gegen Qinlian decoction (GQD) is a traditional Chinese medicine derived from Treatise on febrile diseases and is clinically used for the treatment of acute ulcerative colitis (UC). However, the potential mechanism of GQD treatment for UC remains elusive. AIM OF STUDY: In this study, we aimed to explore the involvement of gut microbiota-related tryptophan metabolism in mediating protective effects of GQD against intestinal barrier damage. MATERIALS AND METHODS: Mice with colitis were treated with 3% dextran sulfate sodium (DSS) for 6 days. The therapeutic effects of GQD in UC mice were examined based on body weight, disease activity index (DAI), organ index, length and pathological changes in the colon. The distribution of fluorescein isothiocyanate dextran (FITC-dextran) in the intestinal tract was observed using small animal imaging, while concentration of FITC-dextran in serum was detected using a fluorescein microplate analyser. Bacterial infiltration in colon tissues was observed by fluorescence in situ hybridisation (FISH), and the bacterial load in mesenteric lymph nodes (MLNs) was further examined through bacterial culture. Subsequently, colonic goblet cells were detected using Alcian blue staining. The tight junctions of the colonic epithelium were observed using transmission electron microscopy, and the expression of tight junction proteins was detected by immunofluorescence (IF) and western blot. In addition, flow cytometry was used to analyse the proportion of interleukin-22-positive (IL-22+) ILC3 cells in lamina propria lymphocytes, and the content of IL-22 in colon homogenates was determined using an ELISA kit. In addition, targeted tryptophan metabolomics was used to detect the concentration of indole derivatives produced by tryptophan metabolism in faeces, and 16S rDNA was used to investigate the composition and abundance of gut microbiota-related tryptophan metabolism. RESULTS: Administration of GQD significantly alleviated the pathological symptoms, including weight loss, increased DAI score, changes in organ index, colon shortening, and colon pathological injury in UC mice. In addition, GQD reduced the diffusion of FITC-dextran in the intestinal tract, the content of FITC-dextran in serum, and bacterial infiltration in MLNs and colon tissues. Additionally, GQD significantly increased the number of colonic goblet cells, repaired the structure of epithelial tight junctions and increased the expression of tight junction proteins. Furthermore, GQD significantly increased the proportion of IL-22+ ILC3 in the lamina propria, the expression of CYP1A1 protein in colon tissue, and the level of IL-22 in colon homogenates. However, the above protective effects of GQD were inhibited by co-administration of GQD and aryl hydrocarbon receptor (AhR) antagonist. Additionally, GQD restored the content of indole derivatives generated by tryptophan metabolism, regulated the diversity of the gut microbiota, and significantly increased the abundance of genes related to tryptophan metabolism. CONCLUSION: Our results confirmed that GQD repaired the damaged intestinal barrier in UC mice by regulating gut microbiota-related tryptophan metabolism and restoring the generation of indole derivatives to activate AhR-mediated IL-22 production.

Wogonin regulates colonocyte metabolism via PPARγ to inhibit Enterobacteriaceae against dextran sulfate sodium-induced colitis in mice.

To investigate the potential effects and mechanism of wogonin on dextran sulfate sodium (DSS)-induced colitis, 70 male mice were administered wogonin (12.5, 25, 50 mg·kg-1 ·d-1 , i.g.) for 10 days, meanwhile, in order to induce colitis, the mice were free to drink 3% DSS for 6 days. We found that wogonin could obviously ameliorate DSS-induced colitis, including preventing colon shortening and inhibiting pathological damage. In addition, wogonin could increase the expression of PPARγ, which not only restores intestinal epithelial hypoxia but also inhibits iNOS protein to reduce intestinal nitrite levels. All these effects facilitated a reduction in the abundance of Enterobacteriaceae in DSS-induced colitis mice. Therefore, compared with the DSS group, the number of Enterobacteriaceae in the intestinal flora was significantly reduced after administration of wogonin or rosiglitazone by 16s rDNA technology. We also verified that wogonin could promote the expression of PPARγ mRNA and protein in Caco-2 cells, and this effect disappeared when PPARγ signal was inhibited. In conclusion, our study suggested that wogonin can activate the PPARγ signal of the Intestinal epithelium to ameliorate the Intestinal inflammation caused by Enterobacteriaceae bacteria expansion.

Laparoscopic Posterior Radical Antegrade Modular Pancreatosplenectomy for Distal Pancreatic Carcinoma.

Distal pancreatic carcinoma is a highly malignant tumor with strong invasiveness, often growing to the edge of the pancreas and penetrating the pancreatic capsule to infiltrate surrounding tissues. In conventional distal pancreatosplenectomy (DPS), tumor cells are prone to spread along the direction of blood and lymphatic reflux due to surgical compression. Additionally, inflammation makes it challenging to achieve R0 resection, leading to a lower patient survival rate. To address these limitations, radical antegrade modular pancreatosplenectomy (RAMPS) was developed, emphasizing deeper excision, including the left anterior renal fascia, the left anterior renal adipose sac, and even the left adrenal gland, to improve the R0 resection rate. With the advancement of minimally invasive surgical techniques, laparoscopic RAMPS (L-RAMPS) is being considered technically safe and feasible in oncology. However, due to technical difficulties and a lack of supporting evidence for clinical application, only a few institutions are currently conducting L-RAMPS. In this context, this article presents detailed techniques for laparoscopic posterior radical antegrade modular pancreatosplenectomy (L-pRAMPS), offering promise for future clinical applications.

Downregulated miRNA-491-3p accelerates colorectal cancer growth by increasing uMtCK expression.

Colorectal carcinoma (CRC) is the second most frequent cancer worldwide. MiR-491-3p, a tumor-suppressive microRNA (miRNA, miR), has been revealed to be abnormally expressed in CRC tissues. Meanwhile, up-regulated ubiquitous mitochondrial creatine kinase (uMtCK) contributes to CRC cell proliferation. Here we aim to explore whether aberrant miR-491-3p expression promotes CRC progression through regulating uMtCK. To this end, miR-491-3p and uMtCK levels were assessed in CRC tissues using quantitative real-time PCR (qRT-PCR). The biological roles of miR-491-3p and uMtCK in regulating CRC growth were evaluated using colony formation assay and mouse Xenograft tumour model. We found that miR-491-3p expression was decreased in CRC tissues compared with matched para-cancerous tissues, whereas uMtCK expression was increased. Functionally, miR-491-3p overexpression repressed SW480 cell growth, whereas miR-491-3p depletion accelerated SW620 cell proliferation and growth. Inversely, uMtCK positively regulated CRC cell proliferation. Mechanistically, miR-491-3p post-transcriptionally downregulated uMtCK expression by binding to 3'-UTR of uMtCK. Consequently, restoring uMtCK expression markedly eliminated the role of miR-491-3p in suppressing CRC growth. Collectively, miR-491-3p functions as a tumour suppressor gene by repressing uMtCK, and may be a potential target for CRC treatment.

The intricate interplay between HIFs, ROS, and the ubiquitin system in the tumor hypoxic microenvironment.

Alterations in protein ubiquitination and hypoxia-inducible factor (HIF) signaling both contribute to tumorigenesis and tumor progression. Ubiquitination is a dynamic process that is coordinately regulated by E3 ligases and deubiquitinases (DUBs), which have emerged as attractive therapeutic targets. HIF expression and transcriptional activity are usually increased in tumors, leading to poor clinical outcomes. Reactive oxygen species (ROS) are upregulated in tumors and have multiple effects on HIF signaling and the ubiquitin system. A growing body of evidence has shown that multiple E3 ligases and UBDs function synergistically to control the expression and activity of HIF, thereby allowing cancer cells to cope with the hypoxic microenvironment. Conversely, several E3 ligases and DUBs are regulated by hypoxia and/or HIF signaling. Hypoxia also induces ROS production, which in turn modulates the stability or activity of HIF, E3 ligases, and DUBs. Understanding the complex networks between E3 ligase, DUBs, ROS, and HIF will provide insights into the fundamental mechanism of the cellular response to hypoxia and help identify novel molecular targets for cancer treatment. We review the current knowledge on the comprehensive relationship between E3 ligase, DUBs, ROS, and HIF signaling, with a particular focus on the use of E3 ligase or DUB inhibitors in cancer.

Effects of motor-cognitive interaction based on dual-task gait analysis recognition in middle age to aging people with normal cognition and mild cognitive impairment.

Background: Mild cognitive impairment (MCI) is considered a transitional stage between cognitive normality and dementia among the elderly, and its associated risk of developing Alzheimer's disease (AD) is 10-15 times higher than that of the general population. MCI is an important threshold for the prevention and control of AD, and intervention in the MCI stage may be the most effective strategy to delay the occurrence of AD. Materials and methods: In this study, 68 subjects who met the inclusion criteria were divided into an MCI group (38 subjects) and normal elderly (NE) group (30 subjects). Both groups underwent clinical function assessments (cognitive function, walking function, and activities of daily living) and dual-task three-dimensional gait analysis (walking motor task and walking calculation task). Spatial-temporal parameters were obtained and reduced by principal component analysis, and the key biomechanical indexes were selected. The dual-task cost (DTC) was calculated for intra-group (task factor) and inter-group (group factor) comparisons. Results: The results of the principal component analysis showed that the cadence parameter had the highest weight in all three walking tasks. In addition, there were significant differences in the cadence both walking motor task (WMT) vs. walking task (WT) and walking calculation task (WCT) vs. WT in the MCI group. The cadence in the NE group only showed a significant difference between WMT and WT. The only differences between the MCI group and NE group was DTC cadence in WCT, and no differences were found for cadence in any of the three walking tasks. Conclusion: The results show that dual tasks based on cognitive-motor gait analysis of DTCcadence in MCI have potential value for application in early identification and provide theoretical support to improve the clinical diagnosis of MCI.

Huang Qin Decoction inhibits the initiation of experimental colitis associated carcinogenesis by controlling the PAD4 dependent NETs.

BACKGROUND: Colorectal cancer is associated with ulcerative colitis (UC). The infiltration of neutrophils is the main cause of DNA damage produced by inflammation in the intestinal epithelium. Under the action of peptidyl arginine deaminase 4 (PAD4), neutrophils dissociate chromatin and form neutrophil extracellular traps (NETs), which can aggravate tissue inflammation and encourage tumor development. Although Huang Qin Decoction (HQD) was found to be useful in treating UC and was used to gradually prevent and treat digestive tract cancers, the underlying reasons were unclear. METHODS: To demonstrate HQD could inhibits the initiation of colitis associated carcinogenesis by controlling NETs related inflammation, we first performed an AOM/DSS-generated colitis-associated carcinogenesis model to assess the efficacy of HQD in reducing neutrophil infiltration and anti-tumor activity. Then, using network pharmacology research, we investigated the potential mechanisms underlying those medicinal effects, as demonstrated by the detection of NETs aggregation and PAD4 expression changes in the colon. RESULTS: HQD substantially reduced the number of colon cancers and the expression of Ki67, restored the level of intestinal tight junction protein occludin and ZO-1, and relieved the intestinal inflammation caused by TNF-α, IL-1ß. At the same time, it inhibited neutrophil infiltration in the colon and improved the immunosurveillance of CD8+T cells. The potential mechanisms of HQD intervention against UC and UC with neoplasia (UCN) were studied using network pharmacology, and 156 conjunct genes as well as numerous inflammation-related pathways were identified. Protein-protein interaction (PPI) analysis indicated that HQD inhibition of intestinal tumors might be related to the deactivation of PAD4, which was verified by the down-regulation of NETs, MPO-DNA complex levels, and PAD4 expression after HQD treatment. CONCLUSION: Huang Qin Decoction inhibits the initiation of colitis associated carcinogenesis by controlling PAD4-dependent neutrophil extracellular traps.