The role of orphan G protein-coupled receptors in pain.

G protein-coupled receptors (GPCRs), which form the largest family of membrane protein receptors in humans, are highly complex signaling systems with intricate structures and dynamic conformations and locations. Among these receptors, a specific subset is referred to as orphan GPCRs (oGPCRs) and has garnered significant interest in pain research due to their role in both central and peripheral nervous system function. The diversity of GPCR functions is attributed to multiple factors, including allosteric modulators, signaling bias, oligomerization, constitutive signaling, and compartmentalized signaling. This review primarily focuses on the recent advances in oGPCR research on pain mechanisms, discussing the role of specific oGPCRs including GPR34, GPR37, GPR65, GPR83, GPR84, GPR85, GPR132, GPR151, GPR160, GPR171, GPR177, and GPR183. The orphan receptors among these receptors associated with central nervous system diseases are also briefly described. Understanding the functions of these oGPCRs can contribute not only to a deeper understanding of pain mechanisms but also offer a reference for discovering new targets for pain treatment.

LncRNA 51325 Alleviates Bone Cancer Induced Hyperalgesia Through Inhibition of Pum2.

Background: Bone cancer pain (BCP) represents one of the most challenging comorbidities associated with cancer metastasis. Long non-coding RNAs (lncRNAs) have garnered attention as potential therapeutic agents in managing neuropathic pain. However, their role in the regulation of nociceptive information processing remains poorly understood. In this study, we observed a significant down-regulation of the spinal lncRNA ENSRNOG00000051325 (lncRNA51325) in a rat model of bone cancer pain. Our study sought to elucidate the potential involvement of lncRNA51325 in the development of BCP by modulating the expression of molecules associated with pain modulation. Methods: We established the BCP model by injecting Walker 256 cells into the tibial plateau of rats. We conducted tests on the pain behaviors and anxiety-like responses of rats through von-Frey test, Gait analysis, and Open Field Test. Spinal lumbar expansion was harvested for molecular biology experiments to explore the relationship between lncRNA51325 and Pumilio RNA binding family member 2 (Pum2). Results: Notably, the overexpression of lncRNA51325 effectively attenuated mechanical allodynia in rats afflicted with BCP, whereas the knockdown of lncRNA51325 induced pain behaviors and anxiety-like responses in naïve rats. Additionally, we observed a time-dependent increase in the expression of Pum2 in BCP-afflicted rats, and intrathecal injection of Pum2-siRNA alleviated hyperalgesia. Furthermore, our investigations revealed that lncRNA51325 exerts a negative modulatory effect on Pum2 expression. The overexpression of lncRNA51325 significantly suppressed Pum2 expression in BCP rats, while the knockdown of lncRNA51325 led to elevated Pum2 protein levels in the spinal cord of naïve rats. Subsequent treatment with Pum2-siRNA mitigated the downregulation of lncRNA51325-induced mechanical allodynia in naïve rats. Conclusion: Our findings indicate that lncRNA51325 plays a role in regulating bone cancer pain by inhibiting Pum2 expression, offering a promising avenue for novel treatments targeting nociceptive hypersensitivity induced by bone metastatic cancer.

miR-199a-3p mediates bone cancer pain through upregulation of dnmt3a expression in spinal dorsal horn neurons.

Due to its complex pathological mechanisms, bone cancer pain (BCP) has become an increasingly challenging clinical issue, there is an urgent need to identify the underlying mechanisms of BCP. In our present study, we found that decreased expression of miR-199a-3p in spinal dorsal horn (SDH) neurons contributed to BCP hypersensitivity. Intrathecal administration of miR-199a-3p agomir alleviated the initiation of tumor inoculation induced pain hypersensitivity and suppressed the expression of DNMT3A. Subsequently, luciferase assays confirmed direct binding between miR-199a-3p and Dnmt3a mRNA. AAV-DNMT3A-shRNA microinjection relieved mechanical hyperalgesia and upregulated the expression of Nrf2 levels in BCP. In naïve rats, Overexpression of DNMT3A yielded the opposite effects. Finally, increase of DNMT3A by lentiviral vector abolished miR-199a-3p-mediated alleviation hypersensitivity effects on BCP progression. Taken these together, our findings highlighted a novel contribution of miR-199a-3p to BCP and provided a fresh outlook on potential mechanism research for BCP.

[Early clinical application and prediction of ROX index in patients with high-flow nasal canula oxygen therapy].

OBJECTIVE: To investigate the application value of ROX index in evaluating the effect of high-flow nasal cannula oxygen therapy (HFNC) on patients diagnosed with respiratory failure, and to find a simpler and more effective method to observe the efficacy of HFNC. METHODS: A retrospective cohort study was conducted. Patients who were admitted to department of critical care medicine of the Tianjin Third Central Hospital from April 2020 to August 2022, diagnosed with type I respiratory failure, and treated with HFNC after failure of conventional oxygen therapy were enrolled. Oxygenation index (PaO2/FiO2), fraction of inspired oxygen (FiO2), gas flow rate at the initial time of admission, and pulse oxygen saturation (SpO2), FiO2 and respiratory rate (RR) at 2, 4, 6, 8, 10 and 12 hours of HFNC were collected, and ROX index was calculated. The patients with symptoms and PaO2/FiO2 improved after HFNC treatment and without higher respiratory support lately were defined as HFNC success, while other patients with symptoms worsening and needing follow-up non-invasive positive pressure ventilation (NIPPV) or invasive positive pressure ventilation (IPPV) were defined as HFNC failure. The tendency of changes in the ROX index at each time point was observed. Receiver operator characteristic curve (ROC curve) was plotted to obtain the optimum cut-off value of ROX index for predicting HFNC outcome and the optimal monitoring time point for HFNC. RESULTS: A total of 142 patients were eventually enrolled, among whom 96 patients (67.61%) were in treated with HFNC successfully, while 46 patients (32.39%) were recorded as HFNC failure (39 patients and 7 patients received NIPPV or IPPV, respectively), with an overall intubation rate of 4.93% (7/142). Compared with the HFNC success group, the HFNC failure group had lower PaO2/FiO2 [mmHg (1 mmHg ≈ 0.133 kPa): 208.8±37.3 vs. 235.7±48.3, P < 0.01] and higher initial gas flow rate (L/min: 46.4±3.9 vs. 42.3±4.9, P < 0.01). However, there was no significant difference in gender, age, primary diagnosis, severity of disease, hemoglobin (Hb), C-reactive protein (CRP), and brain natriuretic peptide (BNP) between the two groups. In the HFNC failure group, there were 12 patients (26.09%) received progressive oxygen therapy within 12 hours of HFNC, of which 3 patients (6.52%) occurred within 6 hours, while the other 9 patients (19.57%) occurred after 6 hours. The initial ROX index was not statistically significant between the two groups. Both groups showed a continuous increasing ROX index with longer treatment duration of HFNC, and the ROX index at all of the time points of the HFNC failure group was significantly lower than that of the HFNC success group with statistically significant difference (2 hours: 9.39±2.85 vs. 10.91±3.51, 4 hours: 8.62±2.29 vs. 11.40±3.18, 6 hours: 7.62±1.65 vs. 11.85±3.45, 8 hours: 7.79±1.59 vs. 11.62±3.10, 10 hours: 7.97±1.62 vs. 12.44±2.75, 12 hours: 8.84±2.51 vs. 12.45±3.03, all P < 0.05). The ROC curve analysis showed that the areas under the ROC curve (AUC) of ROX index assessing the effect of HFNC at the time of treating 6, 8 and 10 hours were better than 2, 4 and 12 hours (0.890, 0.903, 0.930 vs. 0.585, 0.738 and 0.829), indicating that the ROX index could determine the efficacy at the early stage of HFNC (within 6 hours). When the optimum cut-off value of ROX index was 8.78, the sensitivity was 90.6%, and the specificity was 76.5%. CONCLUSIONS: The ROX index at 6 hours of HFNC has a certain predictive value for the efficacy of HFNC with an optimum cut-off value of 8.78, which can provide clinical health care personnel a method for observing the efficacy of HFNC, and guide the correct selection of oxygen therapy modality at an early stage and timely adjustment of oxygen therapy strategy.

JAG-1/Notch signaling axis in the spinal cord contributes to bone cancer pain in rats.

Notch signal plays an important role in regulating cell-cell interactions with the adjacent cells. However, it remains unknown whether Jagged1 (JAG-1) mediated Notch signaling regulates bone cancer pain (BCP) via the spinal cell interactions mechanism. Here, we showed that intramedullary injection of Walker 256 breast cancer cells increased the expression of JAG-1 in spinal astrocytes and knockdown of JAG-1 reduced BCP. The supplementation of exogenous JAG-1 to the spinal cord induced BCP-like behavior and promoted expression of c-Fos and hairy and enhancer of split homolog-1 (Hes-1) in the spinal cord of the naïve rats. These effects were reversed when the rats were administered intrathecal injections of N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT). The intrathecal injection of DAPT reduced BCP and inhibited Hes-1 and c-Fos expression in the spinal cord. Furthermore, our results showed that JAG-1 up-regulated Hes-1 expression by inducing the recruitment of Notch intracellular domain (NICD) to the RBP-J/CSL-binding site located within the Hes-1 promoter sequence. Finally, the intrathecal injection of c-Fos-antisense oligonucleotides (c-Fos-ASO) and administration of sh-Hes-1 to the spinal dorsal horn also alleviated BCP. The study indicates that inhibition of the JAG-1/Notch signaling axis may be a potential strategy for the treatment of BCP.

Epitranscriptomic profiling of N4-acetylcytidine-related RNA acetylation in the spinal dorsal horn of rat with cancer-induced bone pain.

Recently, epigenetics involved in the regulation of gene expression has become a research hotspot. This study evaluated N4-acetylcytidine (ac4c) RNA acetylation in the spinal dorsal horn (SDH) of rats with cancer-induced bone pain (CIBP). The ac4C-specific RIP sequencing and NAT10-specific RIP sequencing were performed to identify the differences in ac4C acetylation and gene expression in the SDH between CIBP and sham groups, the relationship with the acetylation-modifying enzyme NAT10, and association analysis was performed. By interfering with the NAT10 expression, the relationship between some up-regulated genes and ac4C acetylation in CIBP was verified. In this study, we demonstrated that bone cancer increases the levels of NAT10 and the overall acetylation, inducing differential ac4C patterns in the SDH of rats. Through verification experiments, it was found that ac4C acetylation of some genes is regulated by NAT10, and differential ac4C patterns in RNA determine the expression of this RNA. We exposed that some CIBP-related gene expression was altered in the SDH of rats, which was regulated by differentially expressed ac4C acetylation.

Pan-cancer analysis of the prognostic and immunological role of SNX29: a potential target for survival and immunotherapy.

BACKGROUND: There is growing evidence that the SNX family is critical for clinical prognosis, immune infiltration and drug sensitivity in many types of tumors. The relationships between the SNX29 gene and clinical prognosis as well as pan-cancer cell infiltration and drug sensitivity have not been fully elucidated. METHODS: In the current study, we explored the correlation between SNX29 expression and 33 types of malignancies via TCGA and GTEx. The relationship between SNX29 expression and prognostic outcome in the pan-caner cohort was also analyzed. Immune infiltration, microsatellite instability, tumor mutational burden and potential therapeutic targets of SNX29 were investigated by analyzing public databases. RESULTS: The expression of SNX29 was found to be significantly upregulated in most tumor tissues compared to normal tissues. SNX29 expression was associated with prognosis and clinical stage. In the immune infiltration analysis, a significant relationship was found between SNX29 expression and the level of immune infiltration. In addition, we found associations between the SNX29 gene and tumor mutation burden, microsatellite instability, immunoinhibition-related genes and autophagy-related genes. Finally, the expression of SNX29 was significantly associated with the sensitivity of various tumor cell lines to 8 antitumor drugs. These results suggest that SNX29 expression is important in determining the progression, immune infiltration and drug sensitivity of various cancers. CONCLUSION: This study provides novel insights into the potential pan-cancer targets of SNX29.

Upregulation of LncRNA71132 in the spinal cord regulates hypersensitivity in a rat model of bone cancer pain.

ABSTRACT: Bone cancer pain (BCP) is a pervasive clinical symptom which impairs the quality life. Long noncoding RNAs (lncRNAs) are enriched in the central nervous system and play indispensable roles in numerous biological processes, while its regulatory function in nociceptive information processing remains elusive. Here, we reported that functional modulatory role of ENSRNOT00000071132 (lncRNA71132) in the BCP process and sponging with miR-143 and its downstream GPR85-dependent signaling cascade. Spinal lncRNA71132 was remarkably increased in the rat model of bone cancer pain. The knockdown of spinal lncRNA71132 reverted BCP behaviors and spinal c-Fos neuronal sensitization. Overexpression of spinal lncRNA71132 in naive rat generated pain behaviors, which were accompanied by increased spinal c-Fos neuronal sensitization. Furthermore, it was found that lncRNA71132 participates in the modulation of BCP by inversely regulating the processing of miR-143-5p. In addition, an increase in expression of spinal lncRNA71132 resulted in the decrease in expression of miR-143 under the BCP state. Finally, it was found that miR-143-5p regulates pain behaviors by targeting GPR85. Overexpression of miR-143-5p in the spinal cord reverted the nociceptive behaviors triggered by BCP, accompanied by a decrease in expression of spinal GPR85 protein, but no influence on expression of gpr85 mRNA. The findings of this study indicate that lncRNA71132 works as a miRNA sponge in miR-143-5p-mediated posttranscriptional modulation of GPR85 expression in BCP. Therefore, epigenetic interventions against lncRNA71132 may potentially work as novel treatment avenues in treating nociceptive hypersensitivity triggered by bone cancer.

Catalpol ameliorates CFA-induced inflammatory pain by targeting spinal cord and peripheral inflammation.

Chronic, inflammatory pain is an international health concern that severely diminishes individuals' quality of life. Catalpol is an iridoid glycoside derived from the roots of Rehmannia glutinosa that possesses anti-inflammatory, antioxidant, and neuroprotective properties for the treating multiple kinds of disorders. Nevertheless, catalpol's impacts on inflammatory pain and its potential methods of action are still unclear. The purpose of this investigation is to determine the mechanism of catalpol to reduce the inflammatory pain behaviors in a rat model with complete Freund's adjuvant (CFA). Catwalk, Von-Frey, and open field testing were performed for behavioral assessment. Western blot analysis and real-time quantitative PCR (RT-PCR) were employed to identify variations in molecular expression, while immunofluorescence was utilized to identify cellular localization. Catalpol effectively reduced CFA-induced mechanical allodynia and thermal hyperalgesia when injected intrathecally. Moreover, catalpol can regulate the HDAC4/PPAR-γ-signaling pathway in CFA rat spinal cord neurons. Meanwhile catalpol significantly decreased the expression of the NF-κB/NLRP3 inflammatory axis in the spinal cord of CFA rats. In addition, both in vivo and in vitro research revealed that catalpol treatment inhibited astrocyte activation and increase inflammatory factor expression. Interestingly, we also found that catalpol could alleviate peripheral pain by inhibiting tissue inflammation. Taken together, the findings declared that catalpol may inhibit inflammatory pain in CFA rats by targeting spinal cord and peripheral inflammation.

Comparison of clinical efficacy of single-incision and traditional laparoscopic surgery for colorectal cancer: A meta-analysis of randomized controlled trials and propensity-score matched studies.

Background: Single-incision laparoscopy surgery (SILS) is a new laparoscopic technique that has emerged in the past decade. Whether it has advantages over conventionl laparoscopy surgery (CLS) is inconclusive. This article aimed to compare the short- and long-term outcomes of single-incision laparoscopic surgery and conventional laparoscopic surgery for colorectal cancer through high-quality literature text mining and meta-analysis. Methods: Relevant articles were searched on the PubMed, Embase, and Cochrane Library databases from January 2012 to November 2021. All data was from randomized controlled trials (RCTs) in order to increase the confidence of the analytical results.The main outcomes were intraoperative and postoperative complications. Results: A total of 10 RCTs were included, involving 1609 patients. The quality of the included studies was generally high. No significant difference was found between SILS and CLS in the postoperative complications, operation time, postoperative hospital stay, number of lymph nodes removed, readmission, reoperation, complication level I- II, complication level IIIa, complication level IIIb, prolonged Ileus, blood loss, infection, anastomotic leakage and operation time. The results showed that SILS group had a higher rate of intraoperative complications, but it had lower incision length and better cosmetic effects. Conclusion: These results indicate that SILS did not have a comprehensive and obvious advantage over the CLS. On the contrary, SILS has higher intraoperative complications, which may be related to the more difficulty of SILS operation, but SILS still has better cosmetic effects, which is in line with the concept of surgical development. Therefore, the SILS needs to be selected in patients with higher cosmetic requirements and performed by more experienced surgeons.

CXCR1 participates in bone cancer pain induced by Walker 256 breast cancer cells in female rats.

Bone cancer pain (BCP) is a clinically intractable mixed pain, involving inflammation and neuropathic pain, and its mechanisms remain unclear. CXC chemokine receptor 1 (CXCR1, IL-8RA) and 2 (CXCR2, IL-8RB) are high-affinity receptors for interleukin 8 (IL8). According to previous studies, CXCR2 plays a crucial role in BCP between astrocytes and neurons, while the role of CXCR1 remains unclear. The objective of this study was to investigate the role of CXCR1 in BCP. We found that CXCR1 expression increased in the spinal dorsal horn. Intrathecal injection of CXCR1 siRNA effectively attenuated mechanical allodynia and pain-related behaviors in rats. It was found that CXCR1 was predominantly co-localized with neurons. Intrathecal injection of CXCR1-siRNA reduced phosphorylated JAK2/STAT3 protein levels and the NLRP3 inflammasome (NLRP3, caspase1, and IL-1ß) levels. Furthermore, in vitro cytological experiments confirmed this conclusion. The study results suggest that the spinal chemokine receptor CXCR1 activation mediates BCP through JAK2/STAT3 signaling pathway and NLRP3 inflammasome (NLRP3, caspase1, and IL-1ß).

A novel cell senescence-related IncRNA survival model associated with the tumor immune environment in colorectal cancer.

Long noncoding RNAs have a major role in tumorigenesis, development, and metastasis in colorectal cancer (CRC), participate in the regulation of cell senescence and are related to the prognosis of CRC. Therefore, it is important to validate cell senescence-related lncRNAs that correlate with prognosis in CRC. Methods: CRC expression profile data and clinical information were downloaded from TCGA. A gene list related to cellular senescence was obtained from Human Aging Genomic Resources. A coexpression network of cell senescence-related mRNA-lncRNA was explored with R. Six cell senescence-related lncRNA signatures were identified by univariate and multivariate analyses. The cell senescence-related risk model was generated by using six cell senescence-related lncRNAs, and the risk score was calculated. Furthermore, an internal validation set and GSE17537 were used to verify the risk model. The risk model demonstrated good stability and accuracy. Finally, we investigated the correlation between cell senescence-related risk scores and immune infiltration, immune function, immune checkpoints, and drug sensitivity. Result: We established a signature of six cell senescence-related lncRNAs. The cell senescence-related risk model revealed an exceptional ability to assess the prognosis of colorectal cancer and was correlated with clinical features. Additionally, we observed that risk models correlate with the tumor microenvironment and immune checkpoints, potentially predicting patient response to clinical immunotherapy. Finally, we validated the correlation between the cell senescence-related risk model and drug susceptibility. Our findings indicated that AICAR, cisplatin, nilotinib, and bexarotene exhibited lower IC50 values in the high-risk group. Conclusion: Our current study identified 6 cell senescence-associated lncRNA signatures that may be vital biomarkers to predict the prognostic features and immune and chemotherapy responses in CRC.

miR-155-5p in the spinal cord regulates hypersensitivity in a rat model of bone cancer pain.

BACKGROUND: Noncoding microRNAs have emerged as critical players of gene expression in the nervous system, where they contribute to regulating nervous disease. As stated in previous research, the miR-155-5p upregulation happens in the spinal cord at the nociceptive state. It was unclear if miR-155-5p is linked to bone cancer pain (BCP). Herein, we aimed at investigating the miR-155-5p functional regulatory function in BCP process and delineating the underlying mechanism. METHODS: The miRNA-155-5p levels and cellular distribution were determined by RNA sequencing, fluorescent in situ hybridization (FISH), and quantitative real-time PCR (qPCR). Immunoblotting, qPCR, dual-luciferase reporter gene assays, immunofluorescence, recombinant overexpression adeno-associated virus, small interfering RNA, intraspinal administration, and behavioral tests were utilized for exploring the downstream signaling pathway. RESULTS: The miR-155-5p high expression in spinal neurons contributes to BCP maintenance. The miR-155-5p blockage via the intrathecal injection of miR-155-5p antagomir alleviated the pain behavior; in contrast, upregulating miR-155-5p by agomir induced pain hypersensitivity. The miR-155-5p bounds directly to TCF4 mRNA's 3' UTR. BCP significantly reduced protein expression of TCF4 versus the Sham group. The miR-155-5p inhibition relieved the spinal TCF4 protein's down-expression level, while miR-155-5p upregulation by miR-155-5p agomir intrathecal injection decreased TCF4 protein expression in naïve rats. Additionally, TCF4 overexpression in BCP rats could increase Kv1.1. Moreover, TCF4 knockdown inhibited Kv1.1 expression in BCP rats. Indeed, TCF4 and Kv1.1 were co-expressed in BCP spinal cord neurons. CONCLUSION: The study findings stated the miR-155-5p pivotal role in regulating BCP by directly targeting TCF4 in spinal neurons and suggested that miR-155-5p could be a promising target in treating BCP.

Application of apoptosis-related genes in a multiomics-related prognostic model study of gastric cancer.

Gastric cancer (GC) is one of the most common tumors in the world, and apoptosis is closely associated with GC. A number of therapeutic methods have been implemented to increase the survival in GC patients, but the outcomes remain unsatisfactory. Apoptosis is a highly conserved form of cell death, but aberrant regulation of the process also leads to a variety of major human diseases. As variations of apoptotic genes may increase susceptibility to gastric cancer. Thus, it is critical to identify novel and potent tools to predict the overall survival (OS) and treatment efficacy of GC. The expression profiles and clinical characteristics of TCGA-STAD and GSE15459 cohorts were downloaded from TCGA and GEO. Apoptotic genes were extracted from the GeneCards database. Apoptosis risk scores were constructed by combining Cox regression and LASSO regression. The GSE15459 and TCGA internal validation sets were used for external validation. Moreover, we explored the relationship between the apoptosis risk score and clinical characteristics, drug sensitivity, tumor microenvironment (TME) and tumor mutational burden (TMB). Finally, we used GSVA to further explore the signaling pathways associated with apoptosis risk. By performing TCGA-STAD differential analysis, we obtained 839 differentially expressed genes, which were then analyzed by Cox regressions and LASSO regression to establish 23 genes associated with apoptosis risk scores. We used the test validation cohort from TCGA-STAD and the GSE15459 dataset for external validation. The AUC values of the ROC curve for 2-, 3-, and 5-years survival were 0.7, 0.71, and 0.71 in the internal validation cohort from TCGA-STAD and 0.77, 0.74, and 0.75 in the GSE15459 dataset, respectively. We constructed a nomogram by combining the apoptosis risk signature and some clinical characteristics from TCGA-STAD. Analysis of apoptosis risk scores and clinical characteristics demonstrated notable differences in apoptosis risk scores between survival status, sex, grade, stage, and T stage. Finally, the apoptosis risk score was correlated with TME characteristics, drug sensitivity, TMB, and TIDE scores.

A critical role of AMP-activated protein kinase in regulating intestinal nutrient absorption, barrier function, and intestinal diseases.

As one of the most important organs in animals, the intestine is responsible for nutrient absorption and acts as a barrier between the body and the environment. Intestinal physiology and function require the participation of energy. 5'-adenosine monophosphate-activated protein kinase (AMPK), a classical and highly expressed energy regulator in intestinal cells, regulates the process of nutrient absorption and barrier function and is also involved in the therapy of intestinal diseases. Studies have yielded findings that AMPK regulates the absorption of glucose, amino acids, and fatty acids in the intestine primarily by regulating transportation systems, as we detailed here. Moreover, AMPK is involved in the regulation of the intestinal mechanical barrier and immune barrier through manipulating the expression of tight junctions, antimicrobial peptides, and secretory immunoglobulins. In addition, AMPK also participates in the regulation of intestinal diseases, which indicates that AMPK is a promising therapeutic target for intestinal diseases and cancer. In this review, we summarized the current understanding regarding how AMPK regulates intestinal nutrient absorption, barrier function, and intestinal diseases.

Impact of Pain, Agitation, and Delirium Bundle on Delirium and Cognitive Function.

BACKGROUND: Differences in short-term cognitive function between mechanically ventilated patients treated with multicomponent interventions and those receiving routine nursing care have not been established because of the lack of follow-up in previous studies. PURPOSE: This study was designed to evaluate the effects of the pain, agitation, and delirium (PAD) care bundle on delirium occurrence and clinical outcomes, specifically in terms of short-term cognitive function, in mechanically ventilated patients. METHODS: Data on 243 patients with mechanical ventilation were analyzed from January 2017 to February 2019. The eligible patients were divided randomly into two groups. The control group ( n = 120) received usual care, whereas the intervention group ( n = 123) received the PAD bundle, including pain monitoring and management, light sedation and daily awakening, early mobility, sleep promotion, and delirium monitoring. The incidence and duration of delirium, ventilator time, and intensive care unit (ICU) length of stay were compared between the two groups. Upon discharge from the ICU and at 3 and 6 months after discharge, cognitive function was assessed using the Montreal Cognitive Assessment scale and compared between the two groups. RESULTS: The incidence of delirium was reduced significantly in the intervention group, and significant decreases in the duration of delirium, ventilator time, and ICU length of stay were found. Cognitive impairment in the intervention group was significantly lower at the 3-month follow-up assessment. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The PAD bundle was shown to be associated with a lower incidence of delirium and improved clinical outcomes. Short-term cognitive impairment occurred in fewer patients who were managed with the PAD bundle after ICU discharge. Our findings indicate that the PAD bundle has the potential to improve clinical outcomes. The administrative staff of ICUs should use strategies, such as interdisciplinary teamwork, to facilitate the buy-in and implementation of interventions.

Ferroptosis: A Double-Edged Sword in Gastrointestinal Disease.

Ferroptosis is a novel form of regulated cell death (RCD) that is typically accompanied by iron accumulation and lipid peroxidation. In contrast to apoptosis, autophagy, and necroptosis, ferroptosis has unique biological processes and pathophysiological characteristics. Since it was first proposed in 2012, ferroptosis has attracted attention worldwide. Ferroptosis is involved in the progression of multiple diseases and could be a novel therapeutic target in the future. Recently, tremendous progress has been made regarding ferroptosis and gastrointestinal diseases, including intestinal ischemia/reperfusion (I/R) injury, inflammatory bowel disease (IBD), gastric cancer (GC), and colorectal cancer (CRC). In this review, we summarize the recent progress on ferroptosis and its interaction with gastrointestinal diseases. Understanding the role of ferroptosis in gastrointestinal disease pathogenesis could provide novel therapeutic targets for clinical treatment.

Rosiglitazone Alleviates Mechanical Allodynia of Rats with Bone Cancer Pain through the Activation of PPAR-γ to Inhibit the NF-κB/NLRP3 Inflammatory Axis in Spinal Cord Neurons.

Bone cancer pain (BCP) is a serious clinical problem that affects the quality of life of cancer patients. However, the current treatment methods for this condition are still unsatisfactory. This study investigated whether intrathecal injection of rosiglitazone modulates the noxious behaviors associated with BCP, and the possible mechanisms related to this effect were explored. We found that rosiglitazone treatment relieved bone cancer-induced mechanical hyperalgesia in a dose-dependent manner, promoted the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) in spinal cord neurons, and inhibited the activation of the nuclear factor-kappa B (NF-κB)/nod-like receptor protein 3 (NLRP3) inflammatory axis induced by BCP. However, concurrent administration of the PPAR-γ antagonist GW9662 reversed these effects. The results show that rosiglitazone inhibits the NF-κB/NLRP3 inflammation axis by activating PPAR-γ in spinal neurons, thereby alleviating BCP. Therefore, the PPAR-γ/NF-κB/NLRP3 signaling pathway may be a potential target for the treatment of BCP in the future.

Electroacupuncture Attenuates Cancer-Induced Bone Pain via NF-κB/CXCL12 Signaling in Midbrain Periaqueductal Gray.

Electroacupuncture (EA) is effective in various chronic pains. NF-κB and CXCL12 modulate the formation of chronic pain. Herein, we hypothesized that EA alleviates cancer-induced bone pain (CIBP) through NF-κB/CXCL12 axis in midbrain periaqueductal gray (PAG), which participates in "top-down" pain modulatory circuits. In order to filter the optimum EA frequency for CIBP treatment, 2, 100, or 2/100 Hz EA was set up. In addition, ipsilateral, contralateral, and bilateral EA groups were established to affirm the optimal EA scheme. Bilateral 2/100 Hz EA was considered as the optimal therapeutic scheme and was applied in a subsequent experiment. Western blotting along with immunofluorescence illustrated that CIBP induces a rapid and substantial increase in CXCL12 protein level and NF-κB phosphorylation in vlPAG from day 6 to day 12. Anti-CXCL12 neutralizing antibody and pAAV-U6-shRNA(CXCL12)-CMV-EGFP-WPRE in vlPAG remarkably improved the mechanical pain threshold of the hind paw in CIBP model relative to the control. EA inhibited the upregulation of pNF-κB and CXCL12 in vlPAG of CIBP. The recombinant CXCL12 and pAAV-CMV-CXCL12-EF1a-EGFP-3Xflag-WPRE reversed the abirritation of EA in the CIBP rat model. NF-κB phosphorylation mediated-CXCL12 expression contributed to CIBP allodynia, whereas EA suppressed NF-κB phosphorylation in CIBP. According to the above evidence, we conclude that bilateral 2/100 Hz EA is an optimal therapeutic scheme for CIBP. The abirritation mechanism of EA might reduce the expression of CXCL12 by inhibiting the activation of NF-κB, which might lead to the restraint of descending facilitation of CIBP.

Non-coding RNA in drug resistance of gastric cancer.

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide. The poorly prognosis and survival of GC are due to diagnose in an advanced, non-curable stage and with a limited response to chemotherapy. The acquisition of drug resistance accounts for the majority of therapy failure of chemotherapy in GC patients. Although the mechanisms of anticancer drug resistance have been broadly studied, the regulation of these mechanisms has not been completely understood. Accumulating evidence has recently highlighted the role of non-coding RNAs (ncRNAs), including long non-coding RNAs and microRNAs, in the development and maintenance of drug resistance due to their regulatory features in specific genes involved in the chemoresistant phenotype of GC. We review the literature on ncRNAs in drug resistance of GC. This review summarizes the current knowledge about the ncRNAs' characteristics, their regulation of the genes involved in chemoresistance and their potential as targeted therapies for personalized treatment in resistant GC.