Recent insights into the effect of endoplasmic reticulum stress in the pathophysiology of intestinal ischaemia‒reperfusion injury.

Intestinal ischaemia‒reperfusion (I/R) injury is a surgical emergency. This condition is associated with a high mortality rate. At present, there are limited number of efficient therapeutic measures for this injury, and the prognosis is poor. Therefore, the pathophysiological mechanisms of intestinal I/R injury must be elucidated to develop a rapid and specific diagnostic and treatment protocol. Numerous studies have indicated the involvement of endoplasmic reticulum (ER) stress in the development of intestinal I/R injury. Specifically, the levels of unfolded and misfolded proteins in the ER lumen are increased due to unfolded protein response. However, persistent ER stress promotes apoptosis of intestinal mucosal epithelial cells through three signalling pathways in the ER, impairing intestinal mucosal barrier function and leading to the dysfunction of intestinal tissues and distant organ compartments. This review summarises the mechanisms of ER stress in intestinal I/R injury, diagnostic indicators, and related treatment strategies with the objective of providing novel insights into future therapies for this condition.

Effects of perioperative low-dose naloxone on the immune system in patients undergoing laparoscopic-assisted total gastrectomy: a randomized controlled trial.

BACKGROUND: Low immune function after laparoscopic total gastrectomy puts patients at risk of infection-related complications. Low-dose naloxone (LDN) can improve the prognosis of patients suffering from chronic inflammatory diseases or autoimmune diseases. The use of LDN during perioperative procedures may reduce perioperative complications. The purpose of this study was to examine the effects of LDN on endogenous immune function in gastric cancer patients and its specific mechanisms through a randomized controlled trial. METHODS: Fifty-five patients who underwent laparoscopic-assisted total gastrectomy were randomly assigned to either a naloxone group (n = 23) or a nonnaloxone group (n = 22). Patients in the naloxone group received 0.05 µg/kg-1.h- 1naloxone from 3 days before surgery to 5 days after surgery via a patient-controlled intravenous injection (PCIA) pump, and patients in the nonnaloxone group did not receive special treatment. The primary outcomes were the rates of postoperative complications and immune function assessed by NK cell, CD3+ T cell, CD4+ T cell, CD8+ T cell, WBC count, neutrophil percentage, and IL-6 and calcitonin levels. The secondary outcomes were the expression levels of TLR4 (Toll-like receptor), IL-6 and TNF-α in gastric cancer tissue. RESULTS: Compared with the nonnaloxone group, the naloxone group exhibited a lower incidence of infection (in the incision, abdomen, and lungs) (P < 0.05). The numbers of NK cells and CD8+ T cells in the naloxone group were significantly greater than those in the nonnaloxone group at 24 h after surgery (P < 0.05) and at 96 h after surgery (P < 0.05). Compared with those in the nonnaloxone group, the CD3 + T-cell (P < 0.05) and CD4 + T-cell (P < 0.01) counts were significantly lower in the naloxone group 24 h after surgery. At 24 h and 96 h after surgery, the WBC count (P < 0.05) and neutrophil percentage (P < 0.05) were significantly greater in the nonnaloxone group. The levels of IL-6 (P < 0.05) and calcitonin in the nonnaloxone group were significantly greater at 24 h after surgery. At 24 h following surgery, the nonnaloxone group had significantly greater levels of IL-6 (P < 0.05) and calcitonin than did the naloxone group. Compared with those in the naloxone group, the expression levels of TLR4 (P < 0.05) in gastric cancer tissue in the naloxone group were greater; however, the expression levels of IL-6 (P < 0.01) and TNF-α (P < 0.01) in the naloxone group were greater than those in the nonnaloxone group. CONCLUSION: Laparoscopic total gastrectomy patients can benefit from 0.05 ug/kg- 1. h- 1 naloxone by reducing their risk of infection. It is possible that LDN alters the number of cells in lymphocyte subpopulations, such as NK cells, CD3 + T cells, and CD4 + T cells, and the CD4+/CD8 + T-cell ratio or alters TLR4 receptor expression in immune cells, thereby altering immune cell activity. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry on 24/11/2023 (ChiCTR2300077948).

HIF-1α mediates renal fibrosis by regulating metabolic remodeling of renal tubule epithelial cells.

Hypoxia-inducible factor 1-α (HIF-1α) mediates the occurrence and development of renal diseases and fibrosis. In the process, dysregulated cellular metabolism was suggested to be involved in several pathological processes. Here, we found that HIF-1α expression was increased in the early stage of renal fibrosis, and significant metabolic remodeling was triggered. Epigenetic events that drive diseases were characterized previously. Our study showed that ten-eleven translocation-2 (TET2) was upregulated in both renal fibrosis models and metabolite-treated samples. Furthermore, we found that the promoter of α-SMA was hypomethylated at CpG sites, which promoted the expression of α-SMA and the occurrence of renal fibrosis. HIF-1α inhibition alleviated renal fibrosis development by improving metabolic remodeling and TET2 activation. Our studies provide novel insight into HIF-1α-mediated metabolic remodeling in the pathogenesis of renal fibrosis and propose a concept that targets this pathway to treat fibrotic disorders.

MircoRNA-29a in Astrocyte-derived Extracellular Vesicles Suppresses Brain Ischemia Reperfusion Injury via TP53INP1 and the NF-κB/NLRP3 Axis.

Brain ischemia reperfusion injury (BIRI) is defined as a series of brain injury accompanied by inflammation and oxidative stress. Astrocyte-derived extracellular vesicles (EVs) are importantly participated in BIRI with involvement of microRNAs (miRs). Our study aimed to discuss the functions of miR-29a from astrocyte-derived EVs in BIRI treatment. Thus, astrocyte-derived EVs were extracted. Oxygen and glucose deprivation (OGD) cell models and BIR rat models were established. Then, cell and rat activities and pyroptosis-related protein levels in these two kinds of models were detected. Functional assays were performed to verify inflammation and oxidative stress. miR-29a expression in OGD cells and BIR rats was measured, and target relation between miR-29a and tumor protein 53-induced nuclear protein 1 (TP53INP1) was certified. Rat neural function was tested. Astrocyte-derived EVs improved miR-29a expression in N9 microglia and rat brains. Astrocyte-derived EVs inhibited OGD-induced injury and inflammation in vitro, reduced brain infarction, and improved BIR rat neural functions in vivo. miR-29a in EVs protected OGD-treated cells and targeted TP53INP1, whose overexpression suppressed the protective function of EVs on OGD-treated cells. miR-29a alleviated OGD and BIRI via downregulating TP53INP1 and the NF-κB/NLRP3 pathway. Briefly, our study demonstrated that miR-29a in astrocyte-derived EVs inhibits BIRI by downregulating TP53INP1 and the NF-κB/NLRP3 axis.

Exosomes Derived from BMSCs Ameliorate Intestinal Ischemia-Reperfusion Injury by Regulating miR-144-3p-Mediated Oxidative Stress.

BACKGROUND: Intestinal ischemia-reperfusion (I/R) injury is a critical pathophysiological process involved in many acute and critical diseases, and it may seriously threaten the lives of patients. Exosomes derived from bone marrow mesenchymal stem cells (BMSC-exos) may be an effective therapeutic approach for I/R injury. AIMS: This study aimed to investigate the role and possible mechanism of BMSC-exos in intestinal I/R injury in vivo and in vitro based on the miR-144-3p and PTEN/Akt/Nrf2 pathways. METHODS: BMSC-exos were isolated from mouse BMSCs by super centrifugation methods. The effects of BMSC-exos on I/R intestinal injury, intestinal cell apoptosis, oxidative stress and the PTEN/Akt/Nrf2 pathway were explored in vivo and in vitro. Furthermore, the relationship between miR-144-3p and PTEN was confirmed by a dual-luciferase reporter assay. The miR-144-3p mimic and inhibitor were used to further clarify the role of miR-144-3p in the mitigation of intestinal I/R by BMSC-exos. RESULTS: BMSC-exos effectively alleviated intestinal pathological injury, reduced intestinal cell apoptosis, relieved oxidative stress and regulated the PTEN/Akt/Nrf2 pathway in vivo and in vitro. In addition, miR-144-3p was significantly reduced in the oxygen and glucose deprivation/reperfusion cell model, and miR-144-3p could directly target PTEN to regulate its expression. Additional studies showed that changing the expression of miR-144-3p in BMSC-exos significantly affected the regulation of intestinal injury, intestinal cell apoptosis, oxidative stress and the PTEN/Akt/Nrf2 pathway in I/R, suggesting that miR-144-3p in BMSC-exos plays an important role in regulating the PTEN/Akt/Nrf2 during intestinal I/R. CONCLUSIONS: BMSC-exos carrying miR-144-3p alleviated intestinal I/R injury by regulating oxidative stress.

Dexmedetomidine inhibits endoplasmic reticulum stress to suppress pyroptosis of hypoxia/reoxygenation-induced intestinal epithelial cells via activating the SIRT1 expression.

Dexmedetomidine (Dex) can protect the intestine against ischemia/reperfusion (I/R)-induced injury. Sirtuin 1 (SIRT1) pathway, which could be activated by Dex, was reported to inhibit I/R injury. Pyroptosis plays an important role in intestinal diseases. We aimed to investigate whether Dex could attenuate pyroptosis of hypoxia/reoxygenation (H/R)-induced intestinal epithelial cells via activating SIRT1. The intestinal epithelial cell line IEC-6 with or without SIRT1 knockdown after H/R treatment was exposed to Dex, then cell viability, endoplasmic reticulum stress (ERS), apoptosis, pyroptosis, inflammatory cytokines production and SIRT1 expression were detected. Results showed that Dex treatment had no significant effect on IEC-6 cell viability but rescued the H/R-reduced cell viability. The expression of proteins involved in ERS including Grp78, Gadd153 and caspase 12 was enhanced upon H/R stimulation, but was reversely reduced by Dex. The cell apoptosis increased by H/R was also decreased by Dex. Additionally, Dex inhibited pyroptosis and inflammation, which were markedly promoted upon H/R stimulation. The expression of SIRT1, which was reduced after H/R treatment was also partially rescued by Dex. Finally, the above effects of Dex were all blocked by SIRT1 knockdown. In conclusion, Dex could inhibit H/R-induced intestinal epithelial cells ERS, apoptosis and pyroptosis via activating SIRT1 expression.

Determination of cadmium induced acute and chronic reproductive toxicity with Raman spectroscopy.

Cadmium (Cd) is one of the toxic heavy metals which is confirmed to be related to male sterile. Here, confocal Raman spectroscopy was employed to detect biomolecular composition and changes in testis under acute and chronic Cd treatment. Specific Raman shifts associated with mitochondria, nucleic acids, proteins, lipids, and cholesterol were identified which were distinguishing among groups undergoing different Cd treatment times. Supporting evidences were provided by conventional experimental detections. The relevant biochemical parameters, pathological changes, and protein expression related to testosterone synthesis were all changed and consistent with Raman spectrum information. In conclusion, confocal Raman spectroscopy presents a reliable data and provides a novel method which is expected to be a promising strategy in reproduction toxicity research.

Hippocampal astrocyte dysfunction contributes to etomidate-induced long-lasting synaptic inhibition.

Cognitive impairments following the use of general anesthetics are well documented but the underlying mechanisms are unclear. Here, long-lasting cognitive deficits were observed in aged mice following administration of etomidate at a clinically relevant concentration (20 mg/kg); these deficits were closely related to hippocampal synaptic inhibition and astrocyte dysfunction. Using microdialysis and magnetic-activated cell-sorting techniques, we found that astrocyte secretion of glutamate, d-serine, and ATP, as well as astrocyte function, were depressed in the hippocampus following treatment with etomidate. Interestingly, hippocampal astrocyte inhibition (designer receptors exclusively activated by designer drugs; DREADDs) had no effect on the initial synaptic inhibition, but reversed synaptic and cognitive depression in the long term. Furthermore, continual activation of hippocampal astrocytes following administration of a sedative dose (8 mg/kg) of etomidate induced synaptic inhibition and cognitive dysfunction. Our results indicate that general anesthetic-induced hippocampal astrocyte dysfunction plays a role in maintaining synaptic inhibition, which eventually induces long-lasting cognitive deficits.

Application of indocyanine green fluorescence imaging in hepatobiliary surgery.

Indocyanine green (ICG) is a fluorescent dye with an emission wavelength of about 840 nm, which is selectively absorbed by the liver after intravenous or bile duct injection, and then it is excreted into the intestines through the biliary system. With the rapid development of fluorescence laparoscopy, ICG fluorescence imaging is safe, feasible, and widely used in hepatobiliary surgery. ICG fluorescence imaging is of great significance in precise preoperative and intraoperative localization of liver lesions, real-time visualization of hepatic segmental anatomy, intrahepatic and extrahepatic biliary tract visualization, and liver transplantation. ICG fluorescence imaging facilitates efficient intraoperative hepatobiliary decision-making and improves the safety of minimally invasive hepatobiliary surgery. Advances in imaging systems will increase the use of fluorescence imaging as an intraoperative navigation tool, improving the safety and accuracy of open and laparoscopic/robotic hepatobiliary surgery. Herin, we have reviewed the status of ICG applications in hepatobiliary surgery, aiming to provide new insights for the development of hepatobiliary surgery.

Effectiveness and safety of remimazolam tosilate versus propofol for sedation in patients undergoing gastrointestinal endoscopy: a randomized controlled trial.

BACKGROUND: Remimazolam tosilate is a new type of benzodiazepine currently used for gastrointestinal endoscopy and can be combined with alfentanil. AIM: This trial compared the effectiveness and safety of remimazolam with alfentanil to propofol with alfentanil in patients undergoing gastrointestinal endoscopy. METHOD: One hundred and sixty-six patients were randomly divided into propofol-alfentanil anaesthesia (Group P) and remimazolam-alfentanil anaesthesia (Group R). The primary outcomes were perioperative haemodynamic variables, including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR) and oxygen saturation (SpO2) preoperatively (T0); after anaesthesia induction (T1); when the gastroscope passed through the oropharynx (T2); 3 min (T3), 5 min (T4) and 7 min (T5) after T2; at the end of surgery (T6); and when patients successfully awakened (T7). The secondary outcomes included induction and awakening time, patient satisfaction, operator satisfaction, and adverse event occurrences. RESULTS: Compared with those in Group P, the SBP in Group R was significantly higher at T1, T2, T3, and T6 (P < 0.05); the DBP and MAP were significantly higher at T1, T2, T3, T5, and T6 (P < 0.05); the HR was significantly faster at T1 to T6 (P < 0.05); the SpO2 was significantly higher at T1 to T4 (P < 0.05); the incidences of hypoxemia, hypotension, and drug injection pain were significantly lower in Group R (P < 0.05); the incidence of hiccups was higher (P < 0.05); the awakening time was shorter in Group R (P < 0.05); and the operator satisfaction score was high (P < 0.05). CONCLUSION: Compared to propofol with alfentanil, remimazolam with alfentanil can be used safely and effectively for sedation in patients undergoing gastrointestinal endoscopy, with less impact on the patient's circulatory and respiratory systems and a lower incidence of adverse events. TRIAL REGISTRATION: This trial protocol was registered in the Chinese Clinical Trial Registry (ChiCR2300077252, date: 2023-11-02).

Ursolic acid improves necroptosis via STAT3 signaling in intestinal ischemia/reperfusion injury.

Intestinal ischemia/reperfusion injury (IRI) poses a serious threat to human survival and quality of life with high mortality and morbidity rates. The current absence of effective treatments for intestinal IRI highlights the urgent need to identify new therapeutic targets. Ursolic acid (UA), a pentacyclic triterpene natural compound, has been shown to possess various pharmacological properties including intestinal protection. However, its potential protective efficacy on intestinal IRI remains elusive. This study aimed to investigate the effect of UA on intestinal IRI and explore the underlying mechanisms. To achieve this, we utilized network pharmacology to analyze the mechanism of UA in intestinal IRI and assessed UA's effects on intestinal IRI using a mouse model of superior mesenteric artery occlusion/reperfusion and an in vitro model of oxygen-glucose deprivation and reperfusion-induced IEC-6 cells. Our results demonstrated that UA improved necroptosis through the RIP1/RIP3/MLKL pathway, reduced necroinflammation via the HMGB1/TLR4/NF-κB pathway, attenuated morphological damage, and enhanced intestinal barrier function. Furthermore, UA pretreatment downregulated the phosphorylation level of signal transducer and activator of transcription 3 (STAT3). The effects of UA were attenuated by the STAT3 agonist Colivelin. In conclusion, our study suggests that UA can improve intestinal IRI by inhibiting necroptosis in enterocytes via the suppression of STAT3 activation. These results provide a theoretical basis for UA treatment of intestinal IRI and related clinical diseases.

Naringenin alleviates intestinal ischemia/reperfusion injury by inhibiting ferroptosis via targeting YAP/STAT3 signaling axis.

BACKGROUND: Intestinal ischemia/reperfusion injury (IRI) is a significant clinical emergency, and investigating novel therapeutic approaches and understanding their underlying mechanisms is essential for improving patient outcomes. Naringenin (Nar), a flavanone present in tomatoes and citrus fruits, is frequently consumed in the human diet and recognized for having immunomodulatory, anti-inflammatory, and antioxidant properties. Despite Nar being able to alleviate intestinal IRI, the exact molecular mechanisms remain elusive. PURPOSE: To investigate Nar's protective properties on intestinal IRI and elucidate the mechanisms, a comprehensive approach that combines network pharmacology analysis with experimental verification in vitro and in vivo was adopted. METHODS: The oxygen-glucose deprivation/reoxygenation (OGD/R) model in IEC-6 cells and a murine model of intestinal IRI were used. Nar's effects on intestinal IRI were assessed through histological analysis using H&E staining and tight junction (TJ) protein expression. Ferroptosis-related parameters, including iron levels, superoxide dismutase (SOD), glutathione (GSH), reactive oxygen species (ROS), malondialdehyde (MDA), and mitochondrial morphology, were analyzed. Network pharmacology was utilized to predict the pathways through which Nar exerts its anti-ferroptosis effects. Further mechanistic insights were obtained through si-RNA transfection, YAP inhibitor (verteporfin, VP) treatment, ferroptosis inhibitor (Ferrostatin-1) and ferroptosis inducer (Erastin) application, co-immunoprecipitation (Co-IP) and Western blotting. RESULTS: Our results revealed that pretreatment with Nar significantly mitigated intestinal tissue damage and improved gut barrier function, as evidenced by increased TJ proteins (ZO-1 and Occludin). Nar reduced iron, MDA, and ROS, while it increased GSH and SOD levels. Additionally, Nar alleviated mitochondrial damage in mice. Nar treatment increased GPX4 and SLC7A11, while decreasing ACSL4 levels both in vivo and in vitro. Network pharmacology analysis suggested that Nar may target the Hippo signaling pathway. Notably, YAP, a key transcriptional co-activator within the Hippo pathway, was downregulated in intestinal IRI mice and OGD/R-induced IEC-6 cells. Nar pretreatment activated YAP, thereby augmenting anti-ferroptosis effects. The inhibition of YAP activation by VP or YAP knockdown increased p-STAT3 expression, thereby diminishing Nar's efficacy. Co-IP and immunofluorescence studies confirmed the interaction between YAP and STAT3. CONCLUSION: This study shows that Nar can inhibit ferroptosis in intestinal IRI via activating YAP, which in turn suppresses STAT3 phosphorylation, thereby unveiling a novel mechanism and supporting Nar's potential to be a promising therapeutic agent for intestinal IRI.

Molecular Mechanisms of Ferroptosis and Their Involvement in Acute Kidney Injury.

Ferroptosis is a novel way of regulating cell death, which occurs in a process that is closely linked to intracellular iron metabolism, lipid metabolism, amino acid metabolism, and multiple signaling pathways. The latest research shows that ferroptosis plays a key role in the pathogenesis of acute kidney injury (AKI). Ferroptosis may be an important target for treating AKI caused by various reasons, such as ischemia-reperfusion injury, rhabdomyolysis syndrome, sepsis, and nephrotoxic drugs. This paper provides a review on the regulatory mechanisms of ferroptosis and its role in AKI, which may help to provide new research ideas for the treatment of AKI and future research.

Astragalus membranaceus as a Drug Candidate for Inflammatory Bowel Disease: The Preclinical Evidence.

Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that include Crohn's disease (CD) and ulcerative colitis (UC). Today, IBD has no successful treatment. As a result, it is of paramount importance to develop novel therapeutic agents for IBD prevention and treatment. Astragalus membranaceus (AMS) is a traditional Chinese medicine found in the AMS root. Modern pharmacological studies indicate that AMS and its constituents exhibit multiple bioactivities, such as anti-inflammatory, anti-oxidant, immune regulatory, anticancer, hypolipidemic, hypoglycemic, hepatoprotective, expectorant, and diuretic effects. AMS and its active constituents, which have been reported to be effective in IBD treatment, are believed to be viable candidate drugs for IBD treatment. These underlying mechanisms are associated with anti-inflammation, anti-oxidation, immunomodulation, intestinal epithelial repair, gut microbiota homeostasis, and improved energy metabolism. In this review, we summarize the efficacy and underlying mechanisms involved in IBD treatment with AMS and its active constituents in preclinical studies.

Exosomes derived from bone marrow mesenchymal stem cells regulate pyroptosis via the miR-143-3p/myeloid differentiation factor 88 axis to ameliorate intestinal ischemia-reperfusion injury.

Intestinal ischemia-reperfusion (I/R) injury is a condition in which tissue injury is aggravated after ischemia due to recovery of blood supply. Bone marrow mesenchymal stem cell-derived exosome (BMSC-exo) showed a protective effect on I/R injury. This study aimed to investigate the possible mechanisms by which BMSC-exos ameliorate intestinal I/R injury. We isolated mouse BMSC-exos by super-centrifugation and found that they effectively increased cell viability in a cell model, alleviated intestinal barrier injury in a mouse model, and downregulated the expression of inflammatory cytokines and pyroptosis-related proteins, suggesting that BMSC-exos may alleviate intestinal I/R injury in vitro and in vivo by regulating pyroptosis. We identified miR-143-3p as a differentially expressed miRNA by microarray sequencing. Bioinformatic analysis predicted a binding site between miR-143-3p and myeloid differentiation factor 88 (MyD88); a dual-luciferase reporter assay confirmed that miR-143-3p could directly regulate the expression of MyD88. Our findings suggest that miR-143-3p regulates pyroptosis by regulating NOD-like receptor thermal protein domain associated protein 3 (NLRP3) through the toll-like receptor (TLR)-4/MyD88/nuclear factor kappa-B (NF-кB) pathway. This study describes a potential strategy for the treatment of intestinal I/R injury using BMSC-exos that act by regulating pyroptosis through the miR-143-3p mediated TLR4/MyD88/NF-кB pathway.

BMSC-exos ameliorate intestinal ischemia/reperfusion (I/R) injurymiR-143-3p levels were reduced in I/R injury and increased with BMSC-exo treatmentmiR-143-3p directly targeted and downregulated the expression of MyD88BMSC-exos regulate pyroptosis in intestinal I/R injury via the miR-143-3p-MyD88 axis.

Role of Non-coding RNA in the Pathogenesis of Intestinal Ischemia- Reperfusion Injury.

Intestinal ischemia-reperfusion injury is a relatively common clinical condition that seriously threatens the prognosis of patients; however, the exact mechanism of intestinal ischemia-reperfusion injury has not been clarified. Recent studies have found that noncoding RNAs, including but not limited to lncRNA, circRNA, and miRNA, play an important role in the pathogenesis of intestinal ischemia-reperfusion. The findings cited in this paper reveal the expression, function, and mechanism of noncoding RNAs during intestinal ischemia-reperfusion. The mechanistic roles of noncoding RNAs in the occurrence and development of intestinal ischemia-reperfusion are discussed, including cell proliferation, autophagy, oxidative stress, apoptosis, oxidative stress, iron death, and many other aspects. However, many unknown mechanisms of association between noncoding RNAs and intestinal ischemia-reperfusion remain to be investigated.

Role of Circular RNAs in Prostate Cancer.

OBJECTIVES: This study aims to summarize the current literature to demonstrate the importance of circular RNAs (circRNAs) in multiple aspects of prostate cancer (PCa) occurrence, progression, and treatment resistance and explore the potential role in therapeutic strategies aimed at targeting this molecule in PCa. METHODS: The relevant literature from PubMed and Medline databases is reviewed in this article. RESULTS: Non-coding RNA has been proven to play a vital role in regulating tumor progression. Among them, circular RNA plays a more unique role due to its nonlinear structure. Lots of circRNAs were found to be differentially expressed in PCa and regulate cell signaling pathways by regulating particular gene expressions. Recent studies have demonstrated that circRNAs are associated with the chemoresistance of urinary tumors, suggesting that circRNAs might be a novel therapeutic target and a marker for therapeutic response and prognosis assessment. CONCLUSION: The potential crosstalk of circRNAs modifications in PCa development, therapy, and regulation of tumor metabolism is portrayed in this review. However, more preclinical and clinical trials of this targeted strategy are necessary for the treatment of urinary tumors.

Dexmedetomidine against intestinal ischemia/reperfusion injury: A systematic review and meta-analysis of preclinical studies.

BACKGROUND: Intestinal ischemia/reperfusion injury (IRI) is a multifactorial, complex pathophysiological process in clinical settings. In recent years, intestinal IRI has received increasing attention due to increased morbidity and mortality. To date, there are no effective treatments. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, has been demonstrated to be effective against intestinal IRI. In this systematic review and meta-analysis, we evaluated the efficacy and potential mechanisms of DEX as a treatment for intestinal IRI in animal models. METHODS: Five databases (PubMed, Embase, Web of Science, Cochrane Library, and Scopus) were searched until March 15, 2023. Using the SYRCLE risk bias tool, we assessed methodological quality. Statistical analysis was conducted using STATA 12 and R 4.2.2. We analyzed the related outcomes (mucosa damage-related indicators; inflammation-relevant markers, oxidative stress markers) relied on the fixed or random-effects models. RESULTS: There were 15 articles including 18 studies included, and 309 animals were involved in the studies. Compared to the model groups, DEX improved intestinal IRI. DEX decreased Chiu's score and serum diamine oxidase (DAO) level. DEX reduced the level of inflammation-relevant markers (interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α). DEX also improved oxidative stress (decreased malondialdehyde (MDA), increased superoxide dismutase (SOD)). CONCLUSIONS: DEX's effectiveness in ameliorating intestinal IRI has been demonstrated in animal models. Antioxidation, anti-inflammation, anti-apoptotic, anti-pyroptosis, anti-ferroptosis, enhancing mitophagy, reshaping the gut microbiota, and gut barrier protection are possible mechanisms. However, in light of the heterogeneity and methodological quality of these studies, further well-designed preclinical studies are warranted before clinical implication.

Network pharmacology analysis combined with experimental validation to explore the therapeutic mechanism of salidroside on intestine ischemia reperfusion.

ETHNOPHARMACOLOGICAL RELEVANCE: Salidroside (SAL), a phenolic natural product present in Rhodiola rosea, are commonly used in the treatment of various ischemic-hypoxic diseases, including intestinal ischemia-reperfusion (IR) injury. However, their efficacy and potential mechanisms in the treatment of intestinal IR injury have not been investigated. OBJECTIVE: The objective of the present study is to investigate the pharmacological mechanism of action of SAL on intestinal IR injury using a network pharmacology approach combined with experimental validation. METHODS: In the present study, we used the Traditional Chinese Medicine Systematic Pharmacology (TCMSP) database and analysis platform and Comparative Toxicogenomics Database (CTD) to predict possible target genes of SAL, collected relevant target genes of intestinal IR injury from GeneCards and DisGenet websites, and collected summary data to screen common target genes. Then, the protein-protein interaction (PPI) target network was constructed and analyzed by STRING database and Cytoscape 3.8.2 with the above intersecting genes. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed and the component-target-pathway network was constructed, followed by the use of molecular docking and molecular dynamic simulation to verify the possible binding conformation between SAL and candidate targets to further explore the potential targets of SAL in the treatment of intestinal IR injury. Finally, an in vivo model of mouse superior mesenteric artery ligation was established to assess the anti-intestinal IR injury effect of SAL by assessing histopathological changes in mouse small intestine by HE staining, detecting inflammatory factor expression by ELISA kit, and detecting the expression of key protein targets by Western blotting. RESULTS: A total of 166 SAL target genes and 1740 disease-related targets were retrieved, and 88 overlapping proteins were obtained as potential therapeutic targets. The pathway enrichment analysis revealed that the pharmacological effects of SAL on intestinal IR injury were anti-hypoxic, anti-inflammatory and metabolic pathway related, and the molecular docking and molecular dynamic simulation results showed that the core bioactive components had good binding affinity for TXNIP and AMPK, and the immunoblotting results indicated that the expression levels of TXNIP and AMPK in the small intestinal tissues of mice in the drug-treated group compared with the model group were significantly changed. CONCLUSION: SAL may target AMPK and TXNIP domains to act as a therapeutic agent for intestinal IR. These findings comprehensively reveal the potential therapeutic targets for SAL against intestinal IR and provide theoretical basis for the clinical application of SAL in the treatment of intestinal IR.